Risk evaluation and management strategy involving patient follow-ups relating to the use or discontinuation of a complement inhibitor

ABSTRACT

This invention provides, inter alia, a complement-inhibitor-based treatment plan coupled with a risk evaluation and management strategy (“REMS”) and a safety support program (“SSP”) for reinforcing the REMS. The REMS and SPP are implemented using one or more computer devices with software tools programmed to enforce conditions of the REMS and/or prompt follow-ups by registered nurses enrolled in the SSP. The software tool(s) determines whether a prescriber requesting the complement inhibitor has agreed to abide by the REMS, and can prompt a provider of the complement inhibitor to provide updated educational materials to the prescriber at predetermined times or intervals, to monitor the prescriber for compliance with the REMS, and/or to monitor patients for signs of adverse events. Using exemplary embodiments described herein, a risk of adverse events (especially, but not limited to, meningococcal infections) can be managed and an incidence of the adverse events can be reduced.

RELATED APPLICATIONS

This application claims priority to U.S. provisional patent applicationSer. No. 62/080,805, filed Nov. 17, 2014, U.S. provisional patentapplication Ser. No. 62/185,149, filed Jun. 26, 2015, and U.S.provisional patent application Ser. No. 62/208,027, filed Aug. 21, 2015,the contents of which are hereby incorporated by reference.

TECHNICAL FIELD

This invention relates to the fields of immunology and infectiousdisease.

BACKGROUND OF THE INVENTION

Complement is an essential component of the immune system and is ofsubstantial relevance for the destruction of invading microorganisms andfor maintaining tissue homeostasis, including the protection againstautoimmune diseases. Excessive or uncontrolled complement activation,however, significantly contributes to undesired tissue damage.Complement activation presents a considerable risk of harming the hostby directly and indirectly mediating inflammatory tissue destruction.Complement plays a prominent role of in the pathogenesis of numerousinflammatory diseases.

In recent years, great progress has been made in inhibiting complementactivation for potential therapies for complement-relevant diseases. Acertain degree of inhibition of complement activation may be sufficientto reduce its detrimental effects but still preserve the defensemechanisms against invading pathogens. The redundancy of the threecomplement activation pathways may reduce the risk of infection if onlyone pathway is selectively blocked. In addition, the risk of infectiouscomplications is most probably highest when blocking the comparativelyupstream complement component C3. Some complement inhibitors, includingantibodies or antigen-binding fragments specifically recognizing andantagonizing the downstream complement component C5, e.g., eculizumab(Soliris®), have been shown effective in treatment of various diseases.

In some situations, the use and/or discontinuation of a complementinhibitor can lead to an increased risk for adverse events, such asmeningococcal infections, general infections, and hemolysis.

SUMMARY OF THE INVENTION

The present invention provides a solution to the issues discussed aboveby providing systems, methods, and mediums for supporting acomplement-inhibitor-based treatment plan. According to certainembodiments of the invention, the complement-inhibitor-based treatmentplan may be combined with a novel regimen of pre-treatment,intra-treatment, and/or post-treatment follow ups with prescribers andpatients. In practice, this regimen decreases the incidence of adverseevents associated with complement-inhibitor based treatments.

In certain aspects, a method is provided comprising receiving a requestfrom a prescriber to distribute a complement inhibitor and verifyingthat the prescriber has agreed to the following conditions: (a) tovaccinate patients with a Neisseria meningococcal type B specificvaccine, and/or revaccinate patients according to a pre-determinedschedule with a Neisseria meningococcal type B specific vaccine atpredetermined times or intervals, (b) to provide the patients witheducational materials regarding the complement inhibitor, and (c) thatthe prescriber has reviewed information relating to administering thecomplement inhibitor. The claimed method further recites accessing,using a computer with a processor programmed to perform the accessing, adatabase of certified prescribers, and adding, using the processor, theprescriber to the database. The adding to the database is only performedif the prescriber has agreed to conditions (a)-(c).

The claimed method further requires receiving a requisition from theprescriber, the requisition requesting that the prescriber be providedwith the complement inhibitor, inspecting using the processor thedatabase of certified prescribers, and authorizing the prescriber toreceive the complement inhibitor only if the prescriber is in thedatabase of certified prescribers.

In certain aspects, a method is provided for treating a patient in needof treatment with a complement inhibitor, or inhibiting formation ofterminal complement in a patient, comprising administering an effectiveamount of a complement inhibitor to the patient who has been prescribedthe complement inhibitor by a certified prescriber of the complementinhibitor, where a prescriber becomes a certified prescriber of thecomplement inhibitor by first requesting the provider over a network,which is part of a system comprising a computer with a processor, tobecome authorized to prescribe the complement inhibitor, and theprovider then verifies that the prescriber has agreed to the followingconditions:

-   -   (a) to vaccinate and/or revaccinate patients receiving the        complement inhibitor, at predetermined times or intervals, with        one or more meningococcal vaccines, including a Neisseria        meningococcal type B specific vaccine;    -   (b) to provide patients with educational materials regarding the        complement inhibitor, and    -   (c) that the prescriber has reviewed information provided by the        provider relating to the complement inhibitor.        Once verified, adding, using the processor, the prescriber to        the database as a certified prescriber; then using the processor        to generate a prescription approval code and authorizing, using        the processor, the prescriber to prescribe to a patient the        complement inhibitor.

In certain other aspects, a system is provided for a provider of acomplement inhibitor, such as eculizumab or an eculizumab variant, tocommunicate over a network with a prescriber of the complement inhibitorto authorize the prescriber to prescribe a complement inhibitor to apatient in need thereof. The system comprises a computer device. Thecomputer devices includes a processor and a database of the certifiedprescribers of a complement inhibitor. A prescriber becomes a certifiedprescriber of the complement inhibitor by first requesting the providerto become authorized to prescribe the complement inhibitor. Then theprescriber is verified by the provider to be a prescriber that hasagreed to the following conditions: (a) to vaccinate and/or revaccinatepatients receiving the complement inhibitor, at predetermined times orintervals, with one or more meningococcal vaccines, including ameningococcal vaccine to Neisseria meningitidis serogroup B; (b) toprovide patients with educational materials regarding the complementinhibitor, and (c) that the prescriber has reviewed information providedby the provider relating to the complement inhibitor. Once verified, theprocessor adds the prescriber to the database as a certified prescriber.The processor of the computer device can then generate a prescriptionapproval code based on a comparison of an on-line transmission of aprescriber requesting that the prescriber be able to prescribe to apatient the complement inhibitor, with the database of certifiedprescribers, and after using the processor to inspect the database ofcertified prescribers and to ascertain that the prescriber is acertified prescriber, authorize, using the processor, the prescriber toprescribe to a patient the complement inhibitor. The computer devicealso comprises an interface configured to send an on-line transmissionto the prescriber the prescription approval code.

In yet other aspects, a non-transitory computer-readable storage mediumis provided, the medium storing instructions that, when executed by aprocessor of a computer device, cause the processor to: (A) receiveverification that a prescriber requesting to administer a complementinhibitor, such as eculizumab or an eculizumab variant, has agreed tothe following conditions: (a) to vaccinate and/or revaccinate patientsreceiving the complement inhibitor, at predetermined times or intervals,with one or more meningococcal vaccines, including a meningococcalvaccine to Neisseria meningitidis serogroup B; (b) to provide patientswith educational materials regarding eculizumab or an eculizumabvariant, and (c) that the prescriber has reviewed information relatingto administering the complement inhibitor; and (B) access a database ofcertified prescribers; and add the prescriber to the database. Thestorage medium includes instructions that also (C) inspect the databaseof certified prescribers in response to a requisition from theprescriber requesting that the prescriber be provided with eculizumab oran eculizumab variant; and (D) authorizing the prescriber to prescribeeculizumab or an eculizumab variant only if the prescriber is in thedatabase of certified prescribers.

In yet other aspects, a method is provided, comprising: receiving arequest from a patient enrolled in treatment plan of a complementinhibitor, such as eculizumab or an eculizumab variant, to be enrolledin a safety support program; adding, using a computer device with aprocessor suitably programmed to perform the adding, the patient to apatient safety registry; and prompting, using the processor, anauthorized user to follow up with the patient to discuss the possibilityof adverse events associated with the complement inhibitor, theprompting instructing the authorized user to discuss:

-   -   (a) symptoms of the adverse events, and    -   (b) whether the patient has experienced an unreported adverse        event, the prompting performed at one or more predetermined        times or intervals.

Numerous other aspects are provided in accordance with these and otheraspects of the disclosure. Other features and aspects of the presentdisclosure will become more fully apparent from the following drawings,detailed description, and the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A and FIG. 1B depict exemplary network-based embodiments foradministering a complement-inhibitor-based treatment plan.

FIG. 2 depicts an exemplary data structure for storing records in apatient database.

FIG. 3 is a flowchart of an exemplary method to authorize distributionof a drug for use in treating a patient.

FIG. 4 is a flowchart of an exemplary method to receive and storepatient-related data.

FIG. 5 is a flowchart of an exemplary method to compare a symptomexpressed by a patient with an adverse clinical event.

FIG. 6 is a flowchart of an exemplary method to determine whether toauthorize a user access to a drug.

FIG. 7 is a flowchart of an exemplary method to register a patient.

FIG. 8 depicts an exemplary system for implementing an exemplary riskevaluation and management strategy and an exemplary safety supportprogram.

FIG. 9A, FIG. 9B, and FIG. 9C are flowcharts depicting exemplary methodsfor implementing a risk evaluation and management strategy and a safetysupport program.

FIG. 10 is a graph depicting a reduction in meningococcal infectionsfollowing the implementation of an exemplary embodiment describedherein.

FIG. 11 is an exemplary computing device suitable for use with exemplaryembodiments described herein.

DETAILED DESCRIPTION

In certain aspects, a method is provided, comprising receiving a requestfrom a prescriber to distribute a complement inhibitor; verifying thatthe prescriber has agreed to the following conditions: (a) to vaccinatepatients with a Neisseria meningococcal type B specific vaccine, and/orrevaccinate patients according to a pre-determined schedule with aNeisseria meningococcal type B specific vaccine at predetermined timesor intervals, (b) to provide the patients with educational materialsregarding the complement inhibitor, and (c) that the prescriber hasreviewed information relating to administering the complement inhibitor.The method also includes accessing, using a computer with a processorprogrammed to perform the accessing, a database of certifiedprescribers; and adding, using the processor, the prescriber to thedatabase, the adding performed only if the prescriber has agreed toconditions (a)-(c); receiving a requisition from the prescriber, therequisition requesting that the prescriber be provided with thecomplement inhibitor; inspecting, using the processor, the database ofcertified prescribers; and authorizing, using the processor, theprescriber to receive the complement inhibitor only if the prescriber isin the database of certified prescribers.

In certain aspects, a method is provided of treating a patient in needof treatment with a complement inhibitor, or inhibiting formation of aterminal complement in a patient, comprising administering an effectiveamount of a complement inhibitor to the patient who has been prescribedthe complement inhibitor by a certified prescriber of the complementinhibitor; wherein a prescriber becomes a certified prescriber of thecomplement inhibitor by: first requesting the provider over a network,which is part of a system comprising a computer with a processor, tobecome authorized to prescribe the complement inhibitor; the providerthen verifying that the prescriber has agreed to the followingconditions: (a) to vaccinate and/or revaccinate patients receiving thecomplement inhibitor, at predetermined times or intervals, with one ormore meningococcal vaccines, including a Neisseria meningococcal type Bspecific vaccine; (b) to provide patients with educational materialsregarding the complement inhibitor, and (c) that the prescriber hasreviewed information provided by the provider relating to the complementinhibitor. Once verified, adding, using the processor, the prescriber tothe database as a certified prescriber; then using the processor togenerate a prescription approval code and authorizing, using theprocessor, the prescriber to prescribe to a patient the complementinhibitor.

In certain other aspects, a system is provided for a provider of acomplement inhibitor, such as eculizumab or an eculizumab variant, tocommunicate over a network with a prescriber of the complement inhibitorto authorize the prescriber to prescribe a complement inhibitor to apatient in need thereof. The system comprises a computer device. Thecomputer device comprises a processor comprising a database of thecertified prescribers of a complement inhibitor. A prescriber becomes acertified prescriber of the complement inhibitor by first requesting theprovider to become authorized to prescribe the complement inhibitor.Then the prescriber is verified by the provider to be a prescriber thathas agreed to the following conditions: (a) to vaccinate and/orrevaccinate patients receiving the complement inhibitor, atpredetermined times or intervals, with one or more meningococcalvaccines, including a meningococcal vaccine to Neisseria meningitidisserogroup B; (b) to provide patients with educational materialsregarding the complement inhibitor, and (c) that the prescriber hasreviewed information provided by the provider relating to the complementinhibitor. Once verified, the processor adds the prescriber to thedatabase as a certified prescriber. The processor can then generate aprescription approval code based on comparison of an on-linetransmission of a prescriber requesting that the prescriber be able toprescribe to a patient the complement inhibitor, with the database ofcertified prescribers. After using the processor to inspect the databaseof certified prescribers and to ascertain that the prescriber is acertified prescriber, authorize, using the processor, the prescriber toprescribe to a patient the complement inhibitor. The computer devicealso comprises an interface configured to send an on-line transmissionto the prescriber the prescription approval code.

In yet other aspects, a non-transitory computer-readable storage mediumis provided, the medium storing instructions that, when executed by aprocessor of a computer device, cause the processor to (A) receiveverification that a prescriber requesting to administer a complementinhibitor, such as eculizumab or an eculizumab variant, has agreed tothe following conditions: (a) to vaccinate and/or revaccinate patientsreceiving the complement inhibitor, at predetermined times or intervals,with one or more meningococcal vaccines, including a meningococcalvaccine to Neisseria meningitidis serogroup B; (b) to provide patientswith educational materials regarding eculizumab or an eculizumabvariant, and (c) that the prescriber has reviewed information relatingto administering the complement inhibitor; (B) access a database ofcertified prescribers; and add the prescriber to the database; (C)inspect the database of certified prescribers in response to arequisition from the prescriber requesting that the prescriber beprovided with eculizumab or an eculizumab variant; and (D) authorizingthe prescriber to prescribe eculizumab or an eculizumab variant only ifthe prescriber is in the database of certified prescribers.

In yet other aspects, a method is provided, comprising receiving arequest from a patient enrolled in treatment plan of a complementinhibitor, such as eculizumab or an eculizumab variant, to be enrolledin a safety support program; adding, using a computer device with aprocessor suitably programmed to perform the adding, the patient to apatient safety registry; and prompting, using the processor, anauthorized user to follow up with the patient to discuss the possibilityof adverse events associated with the complement inhibitor, theprompting instructing the authorized user to discuss symptoms of theadverse events, and whether the patient has experienced an unreportedadverse event, the prompting performed at one or more predeterminedtimes or intervals.

A Neisseria meningococcal type B specific vaccine can be anymeningococcal vaccine to Neisseria meningitidis serogroup B. In certainembodiments, the Neisseria meningococcal type B specific vaccine ismulticomponent meningococcal serogroup B vaccine (4CMenB or BEXSERO®) ormeningococcal group B vaccine (Neisseria meningitidis serogroup Brecombinant lp2086 a05 protein variant antigen and Neisseriameningitidis serogroup B recombinant lp2086 b01 protein variant antigen,or Trumenba®) (see U.S. Pat. No. 8,563,006).

In certain embodiments, the recommended indication and usage, dosage andadministration, dosage forms and strength, and use in specific patientpopulation of either BEXSERO® or Trumenba® should be followed. However,a healthcare professional may adjust the recommended indication andusage, dosage and administration, dosage forms and strength, and use inspecific patient population of either BEXSERO® or Trumenba® as needed.

According to certain embodiments, a complement-inhibitor-based treatmentplan is coupled with a risk evaluation and management strategy (“REMS”)and a safety support program (“SSP”) for reinforcing the REMS. Usingexemplary embodiments described herein, a risk of adverse events(especially, but not limited to, meningococcal infections) can bemanaged and an incidence of the adverse events can be reduced.

In exemplary embodiments, aspects of the REMS may be monitored andenforced using a software tool. An exemplary REMS software tool canmonitor for, and/or enforce, one or more of the following requirements:

-   -   Mandatory vaccination against meningococcal infection, including        for Neisseria meningitidis serotype B,    -   Performance-linked drug distribution to ensure vaccination of        patients,    -   Direct heightened surveillance with monitoring for early signs        of meningococcal infection, including by Neisseria meningitidis        serotype B, coupled with immediate evaluation of suspected        infection followed by antibiotic treatment, if necessary,    -   Educational materials for both healthcare professionals and        patients regarding infection risks, and/or    -   Evaluation and monitoring of patients who discontinue        complement-inhibitor-based treatment.

Aspects of the SSP may also be monitored and enforced using a softwaretool. The SSP software tool may connect to a database of registerednurses responsible for performing actions under the SSP. An exemplarySSP software tool may prompt one of the registered nurses in thedatabase to perform one or more of the following actions:

-   -   Make calls to patients at predetermined times (e.g., monthly) or        as allowed by the patient to ensure that the patient has a copy        of related patient safety information, to review signs and        symptoms of meningococcal infection, including by Neisseria        meningitidis serotype B, and to encourage the patient to        voluntarily report adverse events to the nurse care manager,        and/or    -   Monitor patient vaccination dates and send a revaccination        reminder letter to the patient's health care provider by 3 years        after the previous vaccination date.

In combination, the REMS and the SSP are effective in encouraging safepractices, such as pre-treatment vaccinations, that can mitigate theoccurrence of adverse events during and after complement-inhibitor-basedtreatment. Another important effect of the REMS and SSP is animprovement in patient understanding of the risks and symptoms ofadverse events. Some adverse events arising from the use of a complementinhibitor require early treatment. However, due to the nature ofcomplement-inhibitor-based treatment, it may be especially difficult toachieve early treatment unless the patient is aware of these symptomsand has the tools to effectively seek early treatment. The REMS and SSPprovide the patient with these tools.

In practice, the incidence of certain kinds of adverse events, such asmeningococcal infections, has been reduced through implementation of theREMS and SSP.

Each of the above-described components (the complement-inhibitor-basedtreatment plan, the REMS software tool, and the SSP software tool) aredescribed in more detail below.

TERMINOLOGY

The present invention is directed to methods for the delivery of drugs,especially drugs inhibiting complement activation pathways, to patients.The term “drug,” as used herein, refers to any substance which isintended for use in the diagnosis, cure, mitigation, treatment orprevention of disease, or to affect the structure or function of thebody. Generally speaking, these methods are desirably and advantageouslyused to educate and reinforce the actions and behaviors of patients whoare taking the drug, as well as prescribers who prescribe the drug andpharmacies which dispense the drug. Such education and reinforcement ofactions and behavior are often necessary to ensure proper prescribingand dispensing of the drug, as well as patient compliance with takingthe drug. In certain cases it is also necessary to educate patients andprescribers concerning discontinuation of the drug. Discontinuation of adrug may lead to harmful effects and the patient and prescriber need tobe educated as to what these harmful effects may be, how to monitor forharmful effects, and how to treat the patient if harmful effects areseen upon discontinuation. A wide variety of educational materials maybe employed to ensure proper prescribing, dispensing, patient complianceand follow-up observation, including, for example, a variety ofliterature and other materials, such as, for example, productinformation, package inserts, educational brochures, continuingeducation monographs, videotapes and the like which may describe therisks and benefits associated with taking and/or discontinuing theparticular drug.

These methods and systems are employed for the distribution of acomplement inhibitor to a patient. The term “complement inhibitor”refers to any agent (e.g., any nucleic acids, amino acids,polynucleotides, polypeptides, proteins, chemical compounds, etc.) whichis capable of at least partially reducing, neutralizing, antagonizing orcompletely inhibiting the activation of complement activation pathways,e.g., the classical pathway, the alternative pathway, and the lectinpathway. Thus, the complement inhibitor can be any inhibitor thatantagonizes any component in the complement activation pathways,resulting in a decreased level of downstream complement activationproducts. For example, a complement inhibitor may generally and broadlyinhibit the complement activation at the level of C1 esterase, C3, orselectively block C5 activation with subsequent inhibition of C5a andC5b-9 (TCC) formation. One example of such inhibitors is an antibody orantigen-binding fragment thereof or antigen-binding polypeptide whichbinds to the cleavage site of C5 and thereby inhibits cleavage of C5 bypreventing the C5 convertase from accessing the cleavage site in C5.Such inhibitors also include an antibody or antigen-binding fragmentthereof or antigen-binding polypeptide, which binds to C5 and inhibitsthe activity of C5a and/or C5b fragment. Another example is an antibodyor antigen-binding fragment thereof which binds to C5 at a site otherthan the cleavage site but prevents cleavage of C5. The antibodieseculizumab and pexelizumab, and variants thereof, are examples of suchantibodies. Other complement inhibitors may antagonize or inhibitactivators of complement pathways. One non-limiting example of suchinhibitors is an antibody, antigen-binding fragment, antigen-bindingpolypeptide, or agent which recognizes and inhibits factor B or factorD. Some naturally occurring regulators include, for example, C1inhibitors, complement receptor 1 (CR1/CD35), complement receptor 2(CR2/CD21), membrane cofactor protein (MCP/CD46), decay-acceleratingfactor (DAF/CD55), factor I, factor H, C4BP, complement receptor 1related gene/protein (Crry), CD59, microbial proteins, etc. Recombinantregulators may also be designed based on the natural regulators. Forexample, soluble proteins (e.g., soluble CR1, DAF, CD59, etc.), taggedproteins (e.g., with a glycosylphosphatidylinositol (GPI) anchor forspecific targeting to cell surface), or fusion proteins comprising atleast one regulator can be constructed and prepared using well-knownmethods in the art. Dominant negative proteins (e.g., containing adominant negative mutation or truncation) of natural regulators can alsobe used as inhibitors of the corresponding endogenous proteins.Furthermore, chimeric proteins containing at least one inhibitor and atleast one other agent (e.g., an agent as a targeting moiety for aspecific cell/tissue type or to increase the stability or efficacy ofthe chimeric protein) could be constructed. In some embodiments, therecombinant complement inhibitor is an antibody or antigen-bindingfragment thereof specifically recognizing at least one complementpathway component, such as, for example, mannose-binding lectin (MBL),C1, C3, C3 convertase, C5, C5 convertase, C5a, C5b-9 (TCC), factor D,factor B, etc. Such specific recognizing and binding by complementinhibitors may lead to an inhibition of the activation of certaincomplement pathway components or the formation of various species, suchas certain protein complexes. The complement inhibitor of thisapplication also includes small molecule inhibitors, for example, C1binding peptides, compstatin, C3aR antagonists, C5aR antagonists, othersmall molecule inhibitors of complement components, etc. For a detaileddiscussion of possible complement inhibitors, see Mollnes andKirschfink, 2006, Strategies of therapeutic complement inhibition,Molecular Immunology 43: 107-121.

In certain embodiments, the complement inhibitor is an antibody (orantigen-binding fragment thereof) that specifically binds to C5 (such ashuman C5). In one embodiment, the antibody or antigen-binding fragmentthereof is the mouse anti-C5 monoclonal antibody BB5.1 (Frei et al.,1987, Mol. Cell. Probes 1: 141-149), the humanized anti-C5 single chainfragment h5G1.1-scFv (i.e., pexelizumab, Alexion Pharmaceuticals,Cheshire, Conn.), or the humanized anti-C5 monoclonal antibodyeculizumab (with the commercial name Soliris®, Alexion Pharmaceuticals,Inc.), or an antigen-binding fragment thereof. Other C5 bindingmolecules and anti-C5 antibodies include, for example, C5 bindingmolecules and anti-C5 antibodies described in U.S. Patent ApplicationPublication Nos. 20100034809 and 20100166748, in U.S. Pat. No.7,999,081, and in Würzner et al. 1991, Complement Inflamm. 8:328-340.

In certain embodiments, the complement inhibitor is a polypeptidecomprising an amino acid sequence with at least about 50% (e.g., 50, 55,60, 65, 70, 75, 80, 85, 90, 95, or above 95%) homology (similarity) oridentity with eculizumab or an eculizumab variant or pexelizumab. Inother embodiments, the complement inhibitor comprises an amino acidsequence with at least about 75% homology or identity with eculizumab oran eculizumab variant or pexelizumab. The complement inhibitor maycomprise in other instances an amino acid sequence with at least about80% homology or identity therewith and in other embodiments at leastabout 85%, 90% or 95% homology or identity therewith. While the term“complement activation” or similar terms used herein in general refersto the activation of at least one of the complement pathways and atleast one of the downstream complement components, the term “inhibitingcomplement activation by antagonizing C5” or similar terms used hereinspecifically refers to inhibiting the cleavage of C5 into C5a and C5b byC5 convertase and inhibiting downstream C5b-9 complex formation orinhibiting the formation of C5a or the activity of C5a.

In certain embodiments, the complement inhibitor is an antigen-bindingfragment of eculizumab or an antigen-binding variant of eculizumab (alsoreferred to herein as an eculizumab variant or a variant eculizumab, orthe like).

In certain embodiments, the complement inhibitor is a variant derivedfrom eculizumab, having one or more improved properties (e.g., improvedpharmacokinetic properties) relative to eculizumab. The varianteculizumab antibody (also referred to herein as an eculizumab variant, avariant eculizumab, or the like) or C5-binding fragment thereof is onethat: (a) binds to complement component C5; (b) inhibits the generationof C5a; and can further inhibit the cleavage of C5 into fragments C5aand C5b. The variant eculizumab antibody can have a serum half-life in ahuman that is greater than, or at least, 10 (e.g., greater than, or atleast, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33 or 34) days. Such variant eculizumabantibodies are described in U.S. Pat. No. 9,079,949.

In yet other embodiments, the C5 inhibitor is LFG316 (Novartis, Basel,Switzerland, and MorphoSys, Planegg, Germany) or another antibodydefined by the sequences of Table 1 in U.S. Pat. No. 8,241,628 and U.S.Pat. No. 8,883,158, ARC1905 (Ophthotech, Princeton, N.J. and New York,N.Y.), which is an anti-C5 pegylated RNA aptamer (see, e.g., Keefe etal., Nature Reviews Drug Discovery 9, 537-550 (July 2010)doi:10.1038/nrd3141), Mubodina® (Adienne Pharma & Biotech, Bergamo,Italy) (see, e.g., U.S. Pat. No. 7,999,081), rEV576 (coversin) (VolutionImmuno-pharmaceuticals, Geneva, Switzerland)(see, e.g., Penabad et al.,Lupus, 2014 October; 23(12):1324-6. doi: 10.1177/0961203314546022.),ARC1005 (Novo Nordisk, Bagsvaerd, Denmark), SOMAmers (SomaLogic,Boulder, Colo.), SOB1002 (Swedish Orphan Biovitrum, Stockholm, Sweden),RA101348 (Ra Pharmaceuticals, Cambridge, Mass.), Aurin TricarboxylicAcid (“ATA”), and anti-C5-siRNA (Alnylam Pharmaceuticals, Cambridge,Mass.), and Ornithodoros moubata C inhibitor (“OmCI”).

The complement inhibitor is designed for treating or preventing acomplement-associated disorder. This invention involves administering toa subject (e.g., a human) in need thereof a therapeutic complementinhibitor (e.g., an antibody or antigen-binding fragment thereof) in anamount sufficient to treat a complement-associated disorder afflictingthe subject.

The complement-associated disorder can be, e.g., a complement-associatedinflammatory disorder, paroxysmal nocturnal hemoglobinuria (PNH),atypical hemolytic uremic syndrome (aHUS), age-related maculardegeneration (AMD), rheumatoid arthritis (RA), myasthenia gravis (MG),neuromyelitis optica (NMO), catastrophic anti-phospholipid syndrome(CAPS), anti-phospholipid syndrome (APS), viral hemorrhagic fever (suchas Ebola hemorrhagic fever), or sepsis. In some embodiments, thecomplement-associated disorder is a complement-associated pulmonarydisorder. For example, the complement-associated pulmonary disorder canbe, e.g., asthma or chronic obstructive pulmonary disease (COPD). Othercomplement-associated disorders are also amenable to treatment orprevention.

The mode of administration can be any suitable mode, and can varydepending on the type of complement-associated disorder to be treatedand the drug to be used. The mode of administration, can be, e.g.,intravenous administration, intrapulmonary administration, intraocularadministration, subcutaneous administration, or intraarticularadministration.

In some embodiments, the complement inhibitor can be administered to apatient in conjunction with other therapies for complement-associateddisorders. For example, the composition can be administered to a subjectat the same time, prior to, or after, plasmapheresis, IVIG therapy, orplasma exchange. See, e.g., Appel et al. (2005) J Am Soc Nephrol16:1392-1404. In some embodiments, the complement inhibitor can beadministered to a subject at the same time, prior to, or after, a kidneytransplant. The other, additional therapies can be any suitable therapy.

A “subject,” as used herein, is a human, and is used interchangeablywith the term “a patient.” In some embodiments, the subject is aninfant, adolescent, or adult.

The meningococcal vaccine to Neisseria meningitidis serogroup B can beany meningococcal vaccine to Neisseria meningitidis serogroup B. Incertain embodiments, the meningococcal vaccine to Neisseria meningitidisserogroup B is BEXSERO® or Trumenba® (see U.S. Pat. No. 8,563,006).

In certain embodiments, the recommended indication and usage, dosage andadministration, dosage forms and strength, and use in specific patientpopulation of either BEXSERO® or Trumenba® should be followed. However,a healthcare professional may adjust the recommended indication andusage, dosage and administration, dosage forms and strength, and use inspecific patient population of either BEXSERO® or Trumenba® as needed.

In certain embodiments, “vaccination,” “administering a vaccine,” or thelike, as used herein, refers to having fully complied with the dosageand frequency of administration as recommended by the manufacturer ofthe vaccine.

As used herein, a subject “in need of prevention,” “in need oftreatment,” or “in need thereof,” refers to one, who by the judgment ofan appropriate medical practitioner (e.g., a doctor, a nurse, or a nursepractitioner in the case of humans; a veterinarian in the case ofnon-human mammals), would reasonably benefit from a given treatment(such as treatment with a composition comprising an anti-C5 antibody orantigen-binding fragment thereof).

The term “preventing” is art-recognized, and when used in relation to acondition, is well understood in the art, and includes administration ofa composition which reduces the frequency of, or delays the onset of,symptoms of a medical condition in a subject relative to a subject whichdoes not receive the composition. Thus, prevention of acomplement-associated disorder such as asthma includes, for example,reducing the extent or frequency of coughing, wheezing, or chest pain ina population of patients receiving a prophylactic treatment relative toan untreated control population, and/or delaying the occurrence ofcoughing or wheezing in a treated population versus an untreated controlpopulation, e.g., by a statistically and/or clinically significantamount.

The terms “therapeutically effective amount,” “effective amount,” or“therapeutically effective dose,” or similar terms used herein areintended to mean an amount of an agent (e.g., a complement inhibitor)that will elicit the desired biological or medical response (e.g., animprovement in one or more symptoms of a complement-associateddisorder).

The term “patient certification” is intended to mean that (a) thepatient, or the legal guardian or representative of the patient, iscompetent to comprehend and assess information and to make decisions;(b) the patient, or the legal guardian or representative of the patient,has received one or both of verbal and written warning as to the risk ofadverse clinical events associated with discontinuing use of thecomplement inhibitor to treat the disorder; and (c) the patient, or thelegal guardian or representative of the patient, has acknowledged thewarning and agreement to the treatment.

The term “antibody” is well known in the art. For example, it refers toa whole or intact antibody (e.g., IgM, IgG, IgA, IgD, or IgE) moleculethat is generated by any one of a variety of methods known in the art.The term “antibody” includes a polyclonal antibody, a monoclonalantibody, a chimerized or chimeric antibody, a humanized antibody, adeimmunized human antibody, and a fully human antibody. The antibody canbe made in or derived from any of a variety of species, e.g., mammalssuch as humans, non-human primates (e.g., monkeys, baboons, orchimpanzees), horses, cattle, pigs, sheep, goats, dogs, cats, rabbits,guinea pigs, gerbils, hamsters, rats, and mice. The antibody can be apurified or a recombinant antibody, from any host cell, such as NS0cells and CHO cells.

As used herein, the term “antibody fragment,” “antigen-bindingfragment,” or similar terms refer to a fragment of an antibody thatretains the ability to bind to an antigen, e.g., a single chain antibody(scFv), an Fd fragment, an Fab fragment, an Fab′ fragment, or an F(ab′)₂fragment. An scFv is a single polypeptide chain that includes both theheavy and light chain variable regions of the antibody from which thescFv is derived. In addition, diabodies (Poljak (1994) Structure2(12):1121-1123; Hudson et al. (1999) J Immunol Methods23(1-2):177-189), minibodies, triabodies (Schoonooghe et al. (2009) BMCBiotechnol 9:70), domain antibodies (also known as “heavy chainimmunoglobulins” or camelids; Holt et al. (2003) Trends Biotechnol21(11):484-490); and intrabodies (Huston et al. (2001) Hum Antibodies10(3-4):127-142; Wheeler et al. (2003) Mol Ther 8(3):355-366; Stocks(2004) Drug Discov Today 9(22): 960-966) are included in the definitionof antibody fragments and can be incorporated into the systems and usedin the methods of this invention.

The antibodies and antigen-binding fragments thereof can be or can bemade “chimeric.” Chimeric antibodies and antigen-binding fragmentsthereof comprise portions from two or more different species (e.g.,mouse and human). Chimeric antibodies can be produced with mousevariable regions of desired specificity fused to human constant domains(for example, U.S. Pat. No. 4,816,567). In this manner, non-humanantibodies can be modified to make them more suitable for human clinicalapplication (e.g., methods for treating or preventing acomplement-mediated disorder in a subject).

Monoclonal antibodies include “humanized” forms of the non-human (e.g.,mouse) antibodies. Humanized or CDR-grafted mAbs are particularly usefulas therapeutic agents for humans because they are not cleared from thecirculation as rapidly as mouse antibodies and do not typically provokean adverse immune reaction. Generally, a humanized antibody has one ormore amino acid residues introduced into it from a non-human source.These non-human amino acid residues are often referred to as “import”residues, which are typically taken from an “import” variable domain.Methods of preparing humanized antibodies are generally well known inthe art.

Complement-Inhibitor-Based Methods

As described above, antibodies and biologically-active fragments can beused to treat a variety of complement-associated disorders such as, butnot limited to: rheumatoid arthritis (RA); lupus nephritis;ischemia-reperfusion injury; paroxysmal nocturnal hemoglobinuria (PNH),atypical hemolytic uremic syndrome (aHUS); typical or infectioushemolytic uremic syndrome (tHUS); myasthenia gravis (MG); neuromyelitisoptica (NMO); antiphospholipid syndrome (APS); Degos disease;catastrophic APS (CAPS); dense deposit disease (DDD); scleroderma;multiple sclerosis (MS); macular degeneration (e.g., age-related maculardegeneration (AMD)); hemolysis, elevated liver enzymes, and lowplatelets (HELLP) syndrome; sepsis; dermatomyositis; diabeticretinopathy; thrombotic thrombocytopenic purpura (TTP); spontaneousfetal loss; Pauci-immune vasculitis; epidermolysis bullosa; recurrentfetal loss; multiple sclerosis (MS); sepsis, viral hemorrhagic fever(such as Ebola hemorrhagic fever), and traumatic brain injury. See,e.g., Holers (2008) Immunological Reviews 223:300-316 and Holers andThurman (2004) Molecular Immunology 41:147-152. Also see PCT PublicationNo. WO2010/054403. In some embodiments, the complement-mediated disorderis a complement-mediated vascular disorder such as, but not limited to,a cardiovascular disorder, myocarditis, a cerebrovascular disorder, aperipheral (e.g., musculoskeletal) vascular disorder, a renovasculardisorder, a mesenteric/enteric vascular disorder, revascularization totransplants and/or replants, vasculitis, Henoch-Schönlein purpuranephritis, systemic lupus erythematosus-associated vasculitis,vasculitis associated with rheumatoid arthritis, immune complexvasculitis, Takayasu's disease, capillary leak syndrome, dilatedcardiomyopathy, diabetic angiopathy, thoracic-abdominal aortic aneurysm,Kawasaki's disease (arteritis), venous gas embolus (VGE), and restenosisfollowing stent placement, rotational atherectomy, and percutaneoustransluminal coronary angioplasty (PTCA). See, e.g., U.S. Pat. No.7,919,094. In some embodiments, the complement-associated disorder ismyasthenia gravis, cold-agglutinin disease (CAD), paroxysmal coldhemoglobinuria (PCH), dermatomyositis, scleroderma, warm autoimmunehemolytic anemia, Graves' disease, Hashimoto's thyroiditis, type Idiabetes, psoriasis, pemphigus, autoimmune hemolytic anemia (AIHA),idiopathic thrombocytopenic purpura (ITP), Goodpasture syndrome,myasthenia gravis (MG), neuromyelitis optica (NMO), antiphospholipidsyndrome (APS), Degos disease, sepsis (including septic shock), viralhemorrhagic fever (such as Ebola hemorrhagic fever) and catastrophic APS(CAPS).

In some embodiments, the complement inhibitor, alone or in combinationwith a second anti-inflammatory agent, can be used to treat aninflammatory disorder such as, but not limited to, RA (above),inflammatory bowel disease, sepsis (above), which includes septic shock,acute lung injury, disseminated intravascular coagulation (DIC), orCrohn's disease. In some embodiments, the second anti-inflammatory agentcan be one selected from the group consisting of nonsteroidalanti-inflammatory drugs (NSAIDs), corticosteroids, methotrexate,hydroxychloroquine, anti-TNF agents such as etanercept and infliximab, aB cell depleting agent such as rituximab, an interleukin-1 antagonist,or a T cell costimulatory blocking agent such as abatacept (marketed asOrencia® by Bristol-Myers Squibb, New York, N.Y.).

In some embodiments, the complement-associated disorder is acomplement-associated neurological disorder such as, but not limited to,amyotrophic lateral sclerosis (ALS), brain injury, Alzheimer's disease,myasthenia gravis (MG), neuromyelitis optica (NMO), and chronicinflammatory demyelinating neuropathy.

Complement-associated disorders also include complement-associatedpulmonary disorders such as, but not limited to, asthma, bronchitis, achronic obstructive pulmonary disease (COPD), an interstitial lungdisease, α-1 anti-trypsin deficiency, emphysema, bronchiectasis,bronchiolitis obliterans, diffuse interstitial lung disease, alveolitis,sarcoidosis, pulmonary fibrosis, and collagen vascular disorders.

In one aspect, the disclosure features treating a patient with thecomplement inhibitor described herein (e.g., an anti-C5 antibody orantigen-binding fragment thereof, such as eculizumab or an eculizumabvariant), wherein the patient is: (i) afflicted with, suspected ofhaving, or at risk for developing a complement-associated disorder(e.g., PNH or aHUS); and (ii) in need of treatment.

In certain embodiments, the anti-C5 antibody for use in methodsdescribed herein is eculizumab. Eculizumab (Soliris®, AlexionPharmaceuticals, Inc.), a humanized monoclonal antibody specificallyrecognizing human complement protein C5 and preventing the cleavage ofC5 and the formation of C5a and the C5b-9 terminal complex, has beendemonstrated to be effective in treating PNH and aHUS patients.

In certain embodiments, the anti-C5 antibody for use in methodsdescribed herein is a variant derived from eculizumab, having one ormore improved properties (e.g., improved pharmacokinetic properties)relative to eculizumab. The variant eculizumab antibody (also referredto herein as an eculizumab variant, a variant eculizumab, or the like)or C5-binding fragment thereof is one that: (a) binds to complementcomponent C5; (b) inhibits the generation of C5a; and can furtherinhibit the cleavage of C5 into fragments C5a and C5b. The varianteculizumab antibody can have a serum half-life in a human that isgreater than, or at least, 10 (e.g., greater than, or at least, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33 or 34) days. Such variant eculizumab antibodies are describedin U.S. Provisional Application No. 61/949,932.

Adverse effects resulting from complement inhibition may be directlyrelated to the function of complement, i.e., increased susceptibility toinfection and autoimmune- and immune-complex diseases, arising fromimpaired opsonization, adaptive immune response, tolerance orelimination of immune-complexes. The risk of infectious complications ismost probably highest when blocking C3. Blocking of C5b-9 formation,however, could lead to increased susceptibility to certain pathogens,such as Neisseriae. In addition, Gram-negative septic shock may resultfrom complement inhibition, while treatment with antibiotics wouldcompensate for short-term complement inhibition.

For Soliris®, meningococcal infections are the most important adversereactions experienced by patients while on the drug. In PNH clinicalstudies, the use of Soliris® increases a patient's susceptibility toserious meningococcal infections (septicemia and/or meningitis). Therisk groups or the most known risk factors include: 1) geneticdeficiency or therapeutic inhibition of terminal complement (such asSoliris® therapy); 2) lack of commercially available vaccine againstmeningococcal serogroup B (now available); and 3) delay or absence ofappropriate medical consultation at the appearance of first symptoms.The occurrence of meningococcal infection can be prevented in some casesby means of meningococcal vaccines. For example, patients without ahistory of meningococcal vaccination can be vaccinated at least 2 weeksprior to receiving the first dose of Soliris® or other complementinhibitor. If urgent Soliris® therapy is indicated in an unvaccinatedpatient, the meningococcal vaccine should be administered as soon aspossible. In patients who cannot receive meningococcal vaccine,including children below the age of two years, antibiotic prophylaxiscould prevent meningococcal infection. However, meningococcalvaccination reduces, but does not eliminate, the risk of meningococcalinfections. In clinical studies, 2 out of 196 PNH patients developedserious meningococcal infections while receiving treatment withSoliris®, both of whom had been vaccinated. In clinical studies amongnon-PNH patients, meningococcal meningitis occurred in one unvaccinatedpatient. In addition, a previously vaccinated patient with aHUSdeveloped meningococcal sepsis during the post-study follow-up period.

Since anti-C5 antibodies or antigen-binding fragments (e.g., eculizumaband pexelizumab) block terminal complement activation, patients treatedwith these agents (e.g., eculizumab/Soliris®) may have increasedsusceptibility to infections in addition to meningococcal infections,especially with encapsulated bacteria. For example, children oradolescent patients may be at increased risk of developing seriousinfections due to Streptococcus pneumonia and Haemophilus influenza typeb (Hib). In clinical studies, a total of 11 out of 195 PNH patientsexperienced an infection-related serious adverse event (SAE) witheculizumab treatment, including Cellulitis (1 patient), Haemophilusinfection (1 patient), other infection (1 patient), Meningococcal sepsis(2 patients), Necrotizing fasciitis (1 patient), respiratory tractinfection (1 patient), urinary tract infection (1 patient), viralinfection (2 patients), and viral upper respiratory tract infection (1patient). One out of 37 aHUS patients treated with eculizumab was foundto have peritonitis. Correspondingly, vaccinations for the prevention ofthese infections should be administered prior to the treatment byterminal complement C5 inhibition.

The Soliris® therapy has been found to increase the number of PNH cells.Actually, the proportion of PNH RBCs increased among Soliris®-treatedPNH patients by a median of 28% from baseline (range from −25% to 69%).Thus, PNH patients who discontinue treatment with Soliris® may be atincreased risk for serious hemolysis. Serious hemolysis is identified byserum lactic dehydrogenase (LDH) levels greater than the pre-treatmentlevel, along with any of the following: greater than 25% absolutedecrease in PNH clone size (in the absence of dilution due totransfusion) in one week or less; a hemoglobin level of <5 gm/dL or adecrease of >4 gm/dL in one week or less; angina; change in mentalstatus; a 50% increase in serum creatinine level; or thrombosis.Therefore, any PNH patient who discontinues Soliris® should be monitoredfor at least 8 weeks to detect serious hemolysis and other reactions. Ifserious hemolysis occurs after Soliris® discontinuation, consider thefollowing procedures/treatments: blood transfusion (packed RBCs), orexchange transfusion (if the PNH RBCs are >50% of the total RBCs) byflow cytometry; anticoagulation; corticosteroids; or reinstitution ofSoliris®. In clinical studies, 16 of 196 PNH patients discontinuedtreatment with Soliris®. Patients were followed for evidence ofworsening hemolysis and no serious hemolysis was observed.

Disclosed herein is an unexpected discovery that some types of adversereactions, including some severe ones, occur after discontinuation ofthe treatment of aHUS patients by inhibiting terminal complement C5. Forexample, severe thrombotic microangiopathy (TMA) complications wereobserved after Soliris® discontinuation in aHUS clinical studies. Thereported severe TMA complications after drug discontinuationincluded: 1) graft failure requiring dialysis; 2) renal insufficiency;3) end stage renal disease; 4) respiratory distress requiringintubation; 5) diarrhea and increased renal insufficiency; and 6)nephrotic syndrome and renal insufficiency. Severe TMA complicationspost discontinuation were identified by (i) any two or more measurementsof any one of the following: a decrease in platelet count of 25% or moreas compared to either baseline or to peak platelet count duringeculizumab treatment; an increase in serum creatinine of 25% or more ascompared to baseline or to nadir during eculizumab treatment; or, anincrease in serum LDH of 25% or more as compared to baseline or to nadirduring eculizumab treatment; or (ii) any one of the following: a changein mental status or seizures; angina or dyspnea; or thrombosis. In aHUSclinical studies, 18 patients (5 in the prospective studies)discontinued Soliris® treatment. Seven (7) severe TMA complications wereobserved following the discontinuation of Soliris® in 5 patients at amedian of 33 days (range 27-80 days) following the last dose. Soliris®treatment was re-initiated in 4 of these 5 patients. However, nofatalities were reported in the aHUS clinical trials as result of severeTMA complications.

Additionally, similar TMA complications post discontinuation have nowbeen seen in patients enrolled in clinical trials evaluating the use ofSoliris® to treat patients who have NMO or MG.

The term “baseline” for different laboratory parameters used in thepresent disclosure is the last value available for the patient prior toinitiation of treatment.

Some clinical parameters may be helpful for laboratory monitoring of PNHand aHUS with or without Soliris® treatment. For example, for PNH, serumLDH levels increase during hemolysis and may assist in monitoringSoliris® effects, including the response to discontinuation of therapy.In clinical studies, six patients achieved a reduction in serum LDHlevels only after a decrease in the Soliris® dosing interval from 14 to12 days. All other patients achieved a reduction in serum LDH levelswith the 14 day dosing interval. For aHUS, early signs of thromboticmicroangiopathy (TMA) include a decrease in platelet count, andincreases in serum LDH and creatinine levels. Thus, patients should befollowed for signs of TMA by monitoring the above laboratory parametersduring Soliris® therapy and/or therapy discontinuation.

If TMA complications occur after Soliris® discontinuation, there-initiation of the drug, with the same or a different regimen (e.g.,dosage, injection method and frequency, etc.) should be considered. Inaddition, other available therapies include, for example, plasma therapy(e.g., plasmapheresis, plasma exchange, fresh frozen plasma infusion,etc.) or appropriate organ-specific supportive measures.

For safety concerns, pharmacovigilance has to be maintained for aHUSpatients. For example, aHUS patients will be registered into a databaseand information regarding their risk factors (e.g., laboratoryparameters regarding aHUS symptoms, related diseases, adverse reactionsduring therapy or after therapy discontinuation, therapy regimens,adverse events or state of well-being) may be collected. The informationin the database may be updated, if necessary, and provided, ifnecessary, to any drug manufacturer, supplier, prescriber, aHUS patient(or the patient's legal guardian, representative, or supervisingpractitioner) as well as regulatory authorities.

The methods disclosed herein involve, inter alia, registering in acomputer readable storage medium prescribers who are qualified toprescribe the involved complement inhibitor drugs including, forexample, eculizumab (Soliris®), pexelizumab, biosimilar equivalents ofeculizumab or pexelizumab, an eculizumab variant, other C5-bindingmolecules and anti-C5 antibodies or antigen-binding fragments thereof,e.g., those disclosed in U.S. Patent Application Publication Nos.20100034809 and 20100166748, in U.S. Pat. No. 7,999,081, and in Würzneret al. Complement Inflamm. 8:328-340 (1991). Once registered in thecomputer readable storage medium, the prescriber, now called a certifiedprescriber, is eligible to prescribe the drug to patients in need of thedrug. Generally speaking, to become registered in the computer readablestorage medium, the prescriber is required to comply with variousaspects of the methods described herein including, for example,providing patient education and counseling, and the like, as describedin detail below. The registration of the prescriber in the computerreadable storage medium may be achieved by providing the prescriber, forexample, by hand, mail, facsimile transmission, or on-line transmission,with a registration card or form, together with appropriate educationalmaterials concerning, for example, the particular drug for which theprescriber is being registered to prescribe, as well as suitable methodsfor delivering the drug to the patient, including the drug deliverymethods described herein. The prescriber completes the registration cardor form by providing information requested therein, and the registrationcard or form is returned to the manufacturer or distributor of the drug,or other authorized recipient of the registration materials, forexample, by hand, mail, facsimile transmission or on-line transmission.Information which may be requested of the prescriber in the registrationcard or form may include, for example, the prescriber's name, address,and affiliation, if any, with one or more health care institutions. Theprescriber's information in the registration card or form is thenentered into the computer readable storage medium. It is contemplatedthat the registration of the prescriber into the computer readablestorage medium may also be achieved, for example, by telephone. Suitablecomputer readable storage media which may be employed for registrationof the prescribers (as well as the pharmacies and patients, as discussedherein) will be apparent to one of ordinary skill in the art, once armedwith the teachings of the present application.

In accordance with the methods described herein, pharmacies which mayfill prescriptions for the particular drug being prescribed herein canalso be registered in a computer readable storage medium. The computerreadable storage medium in which the pharmacies are registered can bethe same as, or different from, the computer readable storage medium inwhich the prescribers are registered. Once registered in the computerreadable storage medium, the pharmacy is eligible to dispense theinvolved drug to patients who are in need of the drug. Generallyspeaking, to become registered in the computer readable storage medium,the pharmacy is required to comply with various aspects of the methodsdescribed herein including, for example, registering the patient (alsocan be done in a computer readable storage medium), as well as otheraspects of the present methods, as described in detail below. As withthe registration of the prescriber in the computer readable storagemedium, the registration of the pharmacy is achieved by providing thepharmacy, for example, by hand, mail, facsimile transmission, or on-linetransmission, with a registration card or form, together withappropriate educational materials concerning, for example, theparticular drug for which the pharmacy is being registered to dispense,as well as suitable methods for delivering the drug to the patient,including the drug delivery methods described herein. The pharmacy thencompletes the registration card or form by providing the informationrequested therein, which thereafter is returned to the manufacturer ordistributor of the drug, or other authorized recipient of theregistration card or form, for example, by hand, mail, facsimiletransmission or on-line transmission. Information which may be requestedof the pharmacy in the registration card or form may include, forexample, the pharmacy's name, address, and affiliation, if any, with anyhealth care institution such as, for example, hospital, health careorganization, and the like. The pharmacy's information in theregistration card or form is then entered into the computer readablestorage medium. It is contemplated that the registration of the pharmacyinto the computer readable storage medium may also be achieved, forexample, by telephone.

As noted above, the drug-distributing methods described herein also caninvolve the registration of the patient in a computer readable storagemedium. The registration of the patient can be carried out by theregistered pharmacy at the time of the patient's initial visit to thepharmacy or by the prescriber if the prescriber obtains the drug andadministers it to the patient. The computer readable storage medium inwhich the patients are registered may be the same as, or different from,the computer readable storage medium in which the prescriber and/orpharmacy is registered. Once registered in the computer readable storagemedium, the patient in need of a particular complement inhibitor drugincluding, for example, a particular anti-C5 antibody or antigen-bindingfragment thereof, may be eligible to receive the drug. Generallyspeaking, to become registered in the computer readable storage medium,the patient is required to comply with various aspects of the methodsdescribed herein. In certain embodiments, the pharmacy or prescriberwill typically have a registration form filled out for the patient,which includes information on the patient, such as the patient's name,mailing address, date of birth, and the like. Information on theprescriber or dispensing pharmacy, such as the information describedabove for the registration thereof, may also be desirably entered on thepatient registration form. The completed form may then be forwarded tothe manufacturer or distributor of the drug, or other authorizedrecipients of the registration form by, for example, hand, mail,facsimile transmission or on-line transmission. It is contemplated thatthe registration of the patient into the computer readable storagemedium may also be achieved, for example, by telephone.

In accordance with the methods of the present disclosure, the deliveryof the drug to the patient may involve the following steps. As a preludeto prescribing and dispensing the drug to the patient, the prescriberand/or the pharmacy are registered in one or more appropriate computerreadable storage media. Suitable computer readable storage mediadescribed herein are apparent to one of ordinary skill in the art, oncearmed with the teachings of the present application. If the prescriberis not registered in the computer readable storage medium, theprescriber is ineligible to prescribe the drug. Similarly, if thepharmacy is not registered in the computer readable storage medium, thepharmacy is ineligible to dispense the drug.

In the course of an examination of a patient, including patientssuffering from one or more diseases and/or disorders relevant tocomplement activation such as, for example, PNH or aHUS, the prescribermay determine that the patient's condition would be improved by theadministration of a drug described herein, including eculizumab(Soliris®) or an eculizumab variant. Prior to prescribing the drug, theprescriber may counsel the patient, for example, on the various risksand benefits associated with the drug. For example, the prescriberpreferably discusses the benefits associated with taking the drug, whilealso advising the patient of the various side effects associatedtherewith. Thus, a patient who may acquire or impart a condition ordisease for which the drug is contraindicated is preferably counseled bythe prescriber on the dangers associated therewith. For example, in thecase of complement inhibitors antagonizing C5 (e.g., eculizumab(Soliris®), an eculizumab variant, pexelizumab, or other anti-C5antibodies described herein), the prescriber may counsel the patient onthe dangers of being administered the drug without vaccination againstvarious bacterial-induced infections (e.g., Meningococcal infection,including an infection by Neisseria meningitidis serotype B) and thedangers of the potential severe hemolysis or severe TMA complicationsafter treatment discontinuation. Such counsel may be provided verbally,as well as in written form. In certain embodiments, the prescriberprovides the patient with literature materials on the drug for which aprescription is contemplated, such as product information, packageinsert, educational brochures, patient instruction videos, and the like.Thus, in the case of methods involving complement inhibitors, theprescriber preferably provides patients with literature information, forexample, in the form of the aforesaid product information, packageinsert, educational brochures, patient instruction videos, and the like,warning the patient of the effects and/or the adverse effects during thetreatment and/or after treatment discontinuation of the inhibitor.

With particular reference to counseling provided in connection with thecomplement inhibitor drug (e.g., eculizumab (Soliris®), an eculizumabvariant, pexelizumab, biosimilar equivalents of eculizumab orpexelizumab, or other anti-C5 antibodies or antigen-binding fragmentsthereof described herein), the prescriber can counsel aHUS patients thathave already discontinued inhibitor treatment or will discontinue thetreatment in future. If the patient has already discontinued theinhibitor treatment or will soon discontinue the treatment (for example,it is reasonably believed that the patient will discontinue thetreatment in 1, 2, 3, 4, 5, 6, 7, or more days, or 1, 2, 3, 4, 5, 6, ormore weeks), the prescriber can counsel and/or remind the patient morefrequently as the expected discontinuation date approaches or after theactual discontinuation date. Further, the patient can be counseled tohave his or her risk factors for the adverse effects afterdiscontinuation (e.g., the various laboratory parameters describedherein) measured by himself/herself, a professional personnel, anorganization, or a facility authorized by the drug supplier, theprescriber, or the distributor (e.g., a nurse, a doctor, a hospital, amedical laboratory, or a pharmacy). The patient can be counseled toexamine his/her risk factors, including for multiple times orcontinuously for a reasonable time period, for identification ofpossible adverse reactions after discontinuation. The drug supplier, theprescriber, and/or the distributor preferably help to provide directionsor such professional personnel or organization for measuring the riskfactors of the patient, preferably periodically.

Once a patient is diagnosed to have, or reasonably predicted to have(e.g., based on various risk factors or laboratory parameters describedherein), at least an adverse effect or reaction after treatmentdiscontinuation, the diagnosis or the reasonable prediction (furtherincluding those measured risk factors or laboratory parameters, if any,in support of such diagnosis or prediction) is registered in a suitablecomputer readable storage medium, which can be in the same registry ofthe patient containing his or her previous clinical information. Thepatient is informed about the diagnostic result or the reasonableprediction (further including those measured risk factors or laboratoryparameters, if any, in support of such diagnosis or prediction). Basedon the registry of the diagnosis or the reasonable prediction, thepatient is counseled for possible treatments or therapies for theadverse reaction. Such possible treatments or therapies include, forexample, re-initiation of the same complement inhibitor treatment ortherapy, substitute treatments or therapies with at least one differentcomplement inhibitor or with a different regimen (e.g., a differentdosage, injection method or frequency, etc.) of the same inhibitor, orsubstitute treatments or therapies involving different mechanisms ortarget molecules causing the disease or the adverse reaction. Forexample, for any adverse reaction experienced or to be experienced(based on reasonable predictions) by an aHUS patient discontinuingSoliris® treatment, the possible treatments or therapies include, forexample, re-initiation of the same Soliris® treatment, a Soliris®treatment with a different regimen, substitute treatments withpexelizumab or a different anti-C5 antibody or antigen-binding fragmentthereof or a different complement inhibitor, or substitute therapiesincluding, for example, plasma therapy (e.g., plasmapheresis, plasmaexchange, fresh frozen plasma infusion, etc.) or appropriateorgan-specific supportive measures. If needed, a combination of thevarious treatments or therapies can be considered and administered tothe patient.

As would be apparent to one of ordinary skill in the art, once armedwith the teachings of the present application, one or more aspects ofthe counseling described above is applicable, in certain circumstances,for complement-inhibiting drugs other than Soliris®, an eculizumabvariant, or other anti-C5 antibodies or antigen-binding fragmentsthereof.

“Counseling a patient” or “counsel a patient” or similar terms usedherein is defined as counseling the patient or the patient's legalguardian(s)/representative(s). For all the counseling situations, thepatient, or the patient's legal guardian(s)/representative(s), should beof age, as well as being in a physical and psychological state capableof apprehending the counseling correctly and precisely. The counselingincludes receiving counseling on the drug being prescribed, andcounseling, for example, on the adverse reactions after treatmentdiscontinuation and prior to receiving a prescription for the drug. Themethods disclosed herein require the patient, or the legal guardian(s)or representative(s) of the patient in case the patient is too young orphysically or mentally incapacitated, to: 1) apprehend the informationcorrectly and precisely; or 2) be legally responsible for his or her ownbehaviors, to express acknowledgment of the counseling and the warningof the adverse reactions while using the drug or discontinuing the usageof the drug. Both the counseling and the acknowledgement can be inverbal and/or written forms. The counseling may be through on-siteconsultation, telephone, mail, facsimile transmission, or on-linetransmission. The counseling may, for example, when a patient is notdirectly supervised by a health professional and/or the prescriber,include literature materials on the drug for which a prescription iscontemplated, such as product information, package insert, educationalbrochures, continuing education monographs, and the like. In certainembodiments, the content of the counseling is provided in the patientlabeling of the drug and is distributed together with the drug. Thepatient, or the legal guardian(s) or representative(s) of the patient,is expected to express acknowledgement of counseling through on-siteacknowledgement, telephone, mail, facsimile transmission, or on-linetransmission, while at least one legally acceptable form ofacknowledgement (for example, an original signature, an electronicsignature, an oath or declaration before a notary, etc.) is submitted.For example, the patient or the patient's legal guardian(s) orrepresentative(s) is expected to fill out an informed consent form whichis signed by the prescriber, as well as the patient or the patient'slegal guardian(s)/representative(s). The prescriber should retain a copyof the informed consent form for his/her records. By filling out andsigning an informed consent form, the patient or the patient's legalguardian(s)/representative(s) acknowledges that he/she understands therisks associated with taking the drug or discontinuing the drug. In theinformed consent form, the patient, or the patient's legal guardian(s)or representative(s) can agree to behave, or help the patient to behave,in a manner which is consistent with the prescriber's counsel. Forexample, in cases involving, for example, anti-C5 antibodies orantigen-binding fragments thereof (e.g., Soliris® and pexelizumab), thepatient, or the patient's legal guardian(s) or representative(s), mayexpress agreement to do, or agreement to help the patient to do, atleast one of the following: i) monitor at least one risk factor orlaboratory parameter for adverse reactions after discontinuing drugtreatment; 2) report to the drug prescriber (including, if needed, thedrug supplier and the drug distributor) the risk factor or laboratoryparameter measurements and the time when the treatment discontinued orwill be discontinued; and 3) consider and, if needed, agree tore-initiate the same treatment or a substitute treatment or therapy asdescribed herein in case of experiencing or expecting to experience(based on reasonable predictions) at least one adverse reaction aftertreatment discontinuation.

In certain embodiments, the counseling described herein is delivered tothe patient, or the patient's legal guardian(s) or representative(s),prior to both a new prescription and any future refill prescription. Anydrug prescriber, distributor, packer, or authorized dispenser can berequired to provide such counseling in one or both verbal and writtenformats (e.g., in the patient labeling) to the patient, or the legalguardian(s) or representative(s) of the patient, when a new prescriptionor refill prescription is dispensed. Any drug manufacturer or suppliercan be further required to: 1) obtain approval from the drug regulatoryagency (e.g., the U.S. FDA office or the corresponding governmentaloffice in the country or region where the drug will be distributed) forthe counseling which will be provided with the drug; and 2) ensure thatthe counseling information will be provided in sufficient numbers, orprovide the means to produce the counseling information in sufficientnumbers, to distributors, packers, and other authorized dispensers topermit these authorized dispensers to provide the counseling informationto each prescriber and to each patient, or the legal guardian(s) orrepresentative(s) of the patient, who will receive a drug prescription.

The counseling information or warning described herein, including, forexample, the potential risk of adverse effects after discontinuing thecomplement inhibitor treatment, can be provided by any drugmanufacturer, supplier, distributor, prescriber, authorized dispenser,or supervising practitioner (e.g., a licensed doctor or nurse or otherpractitioner) to any drug manufacturer, supplier, distributor,prescriber, authorized dispenser, supervising professional personnel, orpatient who is taking or has a potential to take such drug.

A “provider” of a complement inhibitor, such as eculizumab or aneculizumab variant, can be a manufacturer, supplier, and/or distributorof that drug. For example, Alexion Pharmaceuticals is a provider foreculizumab and an eculizumab variant.

As used herein, the term “prescriber” refers to any individual who iscapable of prescribing drugs, including, for example medical doctors.The term “authorized dispenser” used herein is intended to mean anindividual, a facility, or an organization which is licensed,registered, or otherwise permitted by the jurisdiction in which theindividual, facility, or organization practices to provide drug productson prescription in the course of professional practice. Authorizeddispensers have the ability to authorized distribution of the complementinhibitor once the relevant regulatory agencies approve marketing of thecomplement inhibitor. The term “dispense to patients” or “prescriptionis dispensed,” or similar terms used herein are intended to mean the actof delivering a prescription drug to a patient, or the patient's legalguardian(s) or representative(s), either: i) by a licensed practitioneror an agent of a licensed practitioner, either directly or indirectly,for self-administration by the patient, or the patient's legalguardian(s) or representative(s), or outside the licensed practitioner'sdirect supervision; or ii) by an authorized dispenser or an agent of anauthorized dispenser under a lawful prescription of a licensedpractitioner.

In certain embodiments, such counseling information or warning isprovided in the drug label information of the complement inhibitor.Specifically, the prescription drug labeling information is also knownas prescribing information, package insert, professional labeling,direction circular, package circular, etc. The term “label” or similarterms used herein are intended to mean a display of written, printed, orgraphic matter upon the immediate container of any article or meant toinclude a package insert; and a requirement made by or under authorityof U.S. Code of Federal Regulations and the U.S. Federal Food, Drug, andCosmetic Act (FD&C Act) that any word, statement, or other informationappearing on the label shall not be considered to be complied withunless such word, statement, or other information also appears on theoutside container or wrapper, if any there be, of the retail package ofsuch article, or is easily legible through the outside container orwrapper. The term “labeling” or similar terms used herein are intendedto mean all labels and other written, printed, or graphic matters (1)upon any article or any of its containers or wrappers, or (2)accompanying such article, e.g., a package insert.

In certain other embodiments, such counseling information or warning,with or without patient information (e.g., bibliographic information,clinical record, personal and/or family disease and/or therapy record,the risk factors and/or laboratory parameters for disease diagnosingand/or monitoring, etc.) and/or the acknowledgement of the counseling orwarning and agreement to the complement inhibitor treatment from thepatient, are collected and stored, preferably in a database via acomputer readable medium. In still certain other embodiments, suchcollected information is reported fully or partially to any drugmanufacturer, supplier, distributor, prescriber, supervisingprofessional personnel, patients who are taking or have a potential totake such drug, and/or any regulatory agencies (e.g., the U.S. FDA orthe corresponding governmental offices in the country where thecomplement inhibitor is distributed). In certain other embodiments, suchcollected information is updated and/or modified (e.g. with updatedpatient information and/or any change in the acknowledgement andagreement from the patient, or with updated counseling information orwarning based on postmarketing studies or research), preferably in aperiodic manner, and reported as described herein.

The present disclosure also features a database prepared by the methodsdisclosed herein, via a computer readable medium, containing registeredpatients' information. Such patient information may include patientpersonal information (e.g., bibliographic information, personal orfamily disease and/or treatment record, and the fact or potential tohave at least one of the adverse clinical events after discontinuing useof the complement-inhibiting drug) and the patient's acknowledgement ofthe potential adverse reactions after drug discontinuation and agreementto drug treatment as described herein. Such patient information can beupdated, preferably periodically, and be provided to any relevantpersonnel, facility, organization, or authority as described herein.

In certain aspects, a method is provided to distribute a complementinhibitor to a physician or a pharmacy who can further distribute theinhibitor to a patient who needs the complement inhibitor, such ashaving a complement-associated disorder, to treat the patient. In someembodiments, the inhibitor can be authorized for distribution to thephysician or pharmacy only upon certification from the physician orpharmacy that:

i) the physician or pharmacy has received one or both verbal and writtenwarning as to the risk of adverse clinical events associated withdiscontinuing use of the complement inhibitor to treat the disorder; and

ii) the physician or pharmacy will distribute the warning to thepatient, or the legal guardian or representative of the patient.

In certain embodiments, the certification and the information of thephysician or pharmacy can be registered via a computer readable mediuminto a database. The physician or pharmacy can require a certificationor acknowledgement of receiving and understanding of the warningdisclosed herein and/or an agreement of the treatment from the patient,or the legal guardian or representative of the patient prior to or atthe same time of distributing the complement-inhibiting drug to thepatient, or the legal guardian or representative of the patient. Suchcertification or acknowledgement and/or agreement can be furthersubmitted to the drug distributor, manufacturer, and/or regulatoryauthorities, who may register such information into a database via acomputer readable medium. Preferably, such information, including thecertification or acknowledgement and/or agreement from the physician (orpharmacy) or the patient (or the legal guardian or representative of thepatient), or both, is to be received prior to or at the same time of orin a reasonable time frame after distributing the complement-inhibitingdrug to the physician or pharmacy. In one embodiment, the certificationis to be received after the distribution of the inhibitor to thephysician or pharmacy but prior to the distribution of the inhibitor tothe patient, or the legal guardian or representative of the patient.

The present disclosure also features a method of creating a database ofphysicians or pharmacies who can be allowed to distribute a complementinhibitor for use in treating a complement-associated disorder. In someembodiments, the database is registered via a computer readable mediumcontaining information that the physicians or pharmacies have receivedand acknowledged one or both of verbal and written warning as to therisk of adverse clinical events associated with discontinuing use of acomplement inhibitor to treat the disorder and agreed to distributingthe warning to the patient who has the disorder, or the legal guardianor representative of the patient.

In a non-limiting example, the complement-associated disorder disclosedherein is a complement-associated inflammatory disorder, paroxysmalnocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome(aHUS), age-related macular degeneration (AMD), rheumatoid arthritis(RA), myasthenia gravis (MG), neuromyelitis optica (NMO), catastrophicanti-phospholipid syndrome (CAPS), anti-phospholipid syndrome (APS),sepsis, a complement-associated pulmonary disorder, asthma, sepsis,viral hemorrhagic fever (such as Ebola hemorrhagic fever), or chronicobstructive pulmonary disease (COPD).

The present disclosure also features a database of physicians orpharmacies created by the methods disclosed herein.

The present disclosure also features a method to manufacture acomplement inhibitor. The potential manufacturer should obtain anapproval from a relevant government regulatory authority formanufacturing for sale the specific drug for the specific disease orindication. The regulatory authority (including, for example, the U.S.FDA and other corresponding agencies in the country or region where thedrug will be manufactured and/or sold) will make a decision whether toapprove this request based on the previously submitted drug informationincluding, for example, the adverse clinical events after drugdiscontinuation and the patient information comprising the real eventsafter drug discontinuation. Upon approval, the potential manufacturersmay manufacture the complement-inhibiting drug in the approved countryor region. Additionally, the manufacturer may be further required toproduce or ensure the production of a document which provides a warningor caution comprising the whole or part of the information submitted tothe regulatory authority, for example, the adverse clinical events afterdrug discontinuation. The manufacturer may be further required toprovide the manufactured drug together with the produced document to anyrelevant personnel, facility, organization, or authority, if necessary.

The present disclosure also features a method to distribute thecomplement inhibitor described herein. The potential distributor shouldobtain an approval from a relevant government regulatory authority fordistributing the specific drug for the specific disease or indication.The regulatory authority (including, for example, the U.S. FDA or othercorresponding agencies in the country or region where the drug will bedistributed) will make a decision whether to approve this request basedon the previously submitted drug information including, for example, theadverse clinical events after drug discontinuation and the patientinformation comprising the real events after drug discontinuation. Uponapproval, the potential distributor may distribute thecomplement-inhibiting drug in the approved country or region.Additionally, the distributor may be further required to produce orensure the production of a document which provides a warning or cautioncomprising the whole or part of the information submitted to theregulatory authority, for example, the adverse clinical events afterdrug discontinuation. Alternatively, the distributor may receive thedocument from the relevant manufacturer or the authority. Thedistributor may be further required to provide the manufactured drugtogether with the produced document to any relevant personnel, facility,organization, or authority, if necessary.

As used herein, a “memory” refers to the physical devices used to storeprograms or data on a temporary or permanent basis for use in a computeror other digital electronic device. A “computer readable medium” refersto a medium capable of storing data in a format readable by a computeror a computer-related mechanical device. Examples of such computerreadable media include magnetic media such as magnetic disks, cards,tapes, and drums, punched cards and paper tapes, optical disks (e.g.,CD, CD-ROM, CD-R, CD-RW, DVD, etc.), and other media well known in theart. A person of ordinary skill in the art would readily appreciate thata computer readable medium includes a hard drive.

The present disclosure also features a system for distributing thedisclosed complement inhibitor (CI1) for use in treating a patientafflicted with, suspected of having, or at risk for developing acomplement-associated disorder, and in need of treatment with thecomplement inhibitor. As a non-limiting example, the system comprises amemory or a storage device for storing information about the patient andabout whether an instruction to distribute the complement inhibitor isexecuted, and a processor configured to execute the instruction. In someembodiments, the instruction causes the processor to perform the stepscomprising i) searching the memory or storage device for certificationsthat (a) the patient or the legal guardian or representative of thepatient is competent to comprehend and assess information and to makedecisions; (b) the patient, or the legal guardian or representative ofthe patient, has received one or both verbal and written warning as tothe risk of adverse clinical events associated with discontinuing use ofthe complement inhibitor to treat the disorder; and (c) the patient, orthe legal guardian or representative of the patient, has expressedacknowledgment of the warning and agreement to the treatment. Theprocessor also ii) upon the identification of certifications in step i),authorizing distribution of the complement inhibitor to treat thepatient; and iii) registering via the memory or storage device thedistribution of the complement inhibitor.

The systems and methods disclosed herein can be implemented on acomputer system, server, or other electronic device, that is capable ofstoring information or processing information. In some embodiments, thesystem includes one or more computer systems, servers, or otherelectronic devices capable of storing information or processinginformation.

The systems store information on paper or on a computer readable medium.The stored information may include, for example, the basic informationand clinical record of the patient, the information about themanufacturer(s) who will manufacture the complement inhibitor, theinformation about the pharmacy(s) or the physician(s) who willdistribute the complement inhibitor to the patient, the informationabout the distribution of the warning regarding the disclosed adverseclinical events to the patient, the legal guardian or representative ofthe patient, and/or the pharmacy(s) or the physician(s), and theacknowledgement of receiving of such information and/or agreeing to thetreatment by the patient, its legal guardian or representative, and/orthe pharmacy(s) or the physician(s). The system disclosed herein mayfurther store information including, for example, the information aboutthe discontinuing use of the complement inhibitor by the patient, theinformation that the patient is monitored for adverse clinical eventsprior to, at the same time of, or after the discontinuation, and theinformation that the patient is treated by re-initiation of thecomplement inhibitor (CI1) treatment or with an alternative therapy totreat the adverse clinical events after the discontinuing use of thecomplement inhibitor (CI1).

The information stored in the system disclosed herein can be collectedin a voluntary or mandatory manner from the corresponding patient (orhis or her legal guardian or representative), the manufacturer ordistributor of the complement inhibitor, and/or the pharmacy or thephysician who will distribute the complement inhibitor to the patient.The information can be stored and created, for example, into a database.The information can be reported to a government regulatory agency in avoluntary or mandatory manner. In some embodiments, a review of suchreported information followed by an approval from the governmentregulatory agency is required prior to the distribution of thecomplement inhibitor. The collection and/or the submission of theinformation disclosed herein can be executed by hand, mail, telephone,facsimile transmission, or on-line transmission.

These and other embodiments of the invention are described below withreference to FIGS. 1-11 wherein like numerals are used throughout todenote like elements.

FIGS. 1A and 1B depict example network and database structures that maybe used to implement the systems and methods disclosed herein andcomprise systems 100 and 130. In particular, FIG. 1A is a block diagramof a computerized system 100 for authorizing the distribution of a drugto patients, according to an illustrative implementation. The system 100includes a server 104 and for example and in a non-limiting way aselected number, such as three, user devices 110A-110C (generally, userdevice 110) connected over a network 102 to the server 104. The server104 includes a processor 105 and an electronic database 106, and eachuser device 110 includes a processor 112 and a user interface 114, suchas user interfaces 114A, 114B and 114C. As used herein, the term“processor” or “computing device” refers to one or more electronicdevices, computing devices, computers, microprocessors, logic devices,servers, smart phones, tablets, or other devices configured withhardware, firmware, and/or software to carry out one or more of thecomputerized techniques described herein. Processors and processingdevices may also include one or more memory devices for storing inputs,outputs, and data that is currently being processed. An illustrativecomputing device 1100, which may be used to implement any of theprocessors and servers described herein, is described in detail belowwith reference to FIG. 11. As used herein, “user interface” includes,without limitation, any suitable combination of one or more inputdevices (e.g., keypads, displays, touch screens, trackballs, voicerecognition systems, and the like) and/or one or more output devices(e.g., visual displays, speakers, tactile displays, printing devices,and the like). As used herein, “user device” includes, withoutlimitation, any suitable combination of one or more devices configuredwith hardware, firmware, and software to carry out one or more of thecomputerized techniques described herein. Examples of user devicesinclude, without limitation, personal computers, laptops, and mobiledevices (such as smartphones, blackberries, PDAs, tablet computers, andthe like). One server and three user devices are shown in FIG. 1A.However, the arrangement and number of components shown in FIG. 1A aremerely illustrative, and the system 100 can support multiple servers andany number of user devices in any suitable configuration.

The components of the system 100 of FIG. 1A may be arranged,distributed, and combined in any of a number of ways. For example, thecomponents of system 100 may be distributed over multiple processing andstorage devices connected via the network 102. Such an implementationmay be appropriate for distributed computing over multiple communicationsystems including wireless and wired communication systems that shareaccess to a common network resource. In some implementations, system 100is implemented in a cloud computing environment in which one or more ofthe components are provided by different processing and storage servicesconnected via the Internet or other communications system. For example,the server 104 may be implemented as virtual servers instantiated in acloud computing environment. The electronic database 106 may be adistributed system of databases that includes data regarding patientinformation such as a patient's demographic features (such as date ofbirth, gender, height, weight, or any other demographic feature),diagnosis, prognosis, administered medications, symptoms, physicians,pharmacists, geographical location, or any other suitable data relatedto a patient. The improved availability associated with usingdistributed architecture advantageously facilitates continuous trackingand logging of inputs from various patients, physicians, pharmacists, orany other suitable representative of a patient.

The components of FIG. 1A may be implemented as one or more componentsincluded with or local to a user device 110. For example, FIG. 1Adepicts a user device 110 that includes a processor 112 and a userinterface 114. The processor 112 may be configured to perform any of thefunctions described herein for the user interface 114. Additionally, thefunctions performed by each of the components in system 100 may berearranged. In some implementations, the processor 112 may perform someor all of the functions of the processor 105 as described herein. Anysuitable variation of this system may be used.

A user provides user input over the user interface 114. The user may bethe patient or a representative of the patient such as a legal guardian,physician, pharmacist, or nurse. The user input may include any datarelated to a patient. In particular, the user input includes dataindicative of the patient's identity, such as the patient's name or anidentification number associated with the patient such as a socialsecurity number, a healthcare insurance number, and the like. Theprocessor 112 transmits this data over the network 102 to the server104, and the processor 105 parses the electronic database 106 for aprevious registration of the patient.

If the patient has been previously registered, the user provides dataindicative of an event in the patient's care. For example, an event mayinclude an administration of a drug, a symptom expressed by the patient,a measurement of a level of physiological parameter related to thepatient, or any other suitable event (e.g., an adverse clinical event)related to the care of the patient. The event data is then transmittedover the network 102, received by the processor 105, and stored in theelectronic database 106.

Alternatively, if the patient has not been previously registered, theuser device 110 is configured to prompt the user to register thepatient. Registration of a patient may require several electroniccertifications over the user interface 114, including a certificationthat a representative of the patient is competent and can make decisionsregarding the patient's treatment. In addition, the representativereceives a warning regarding the risk of adverse clinical eventsassociated with the use of a drug to treat the patient. Another possiblerequired certification for registration of the patient is that therepresentative has acknowledged receipt of the warning. A third possiblecertification requires that the representative agrees to use the drug intreatment for the patient.

When registration is complete at the user interface 114, the processor112 transmits the new patient's data over the network 102 to the server104, where the data is stored in the electronic database 106 as aregistered patient. Then, the processor 105 updates an electronicauthorization variable associated with the registered patient, therebyauthorizing distribution of the drug for use in treating the patient.The same user device 110 may be used to register different patients.Similarly, data regarding a given patient may be provided over multipleuser devices 110 over the course of the patient's treatment. In thisway, system 100 provides a secure method of authorizing distribution ofa drug to patients with representatives who acknowledge a risk ofadverse clinical events associated with the drug.

The components of system 130 illustrated in FIG. 1B are similar to thoseof FIG. 1A, with the exception that FIG. 1B additionally includes ahealthcare service provider system 116 including a processor 118 and anelectronic database 120. In some implementations, the healthcare serviceprovider system 116 is configured to share patient-related data storedon the electronic database 120 with the server 104. In particular, thehealthcare service provider system 116 may have additional dataregarding a registered patient that have not been directly provided by auser device 110. For example, the user device 110 may have been used toregister a patient for a particular disorder. At a later time, the samepatient may be treated at a hospital for a different disorder, and thehospital may monitor patient treatments and symptoms. The hospital staffmay have provided data indicative of the patient's treatment and/orsymptoms to the healthcare service provider system 116, which stores thedata on the electronic database 120. The data on the electronic database120 is then shared with the server 104. By aggregating patient-relateddata across different sources, the server 104 is more likely to maintainan updated patient history and achieves a more accurate patient profile.

The patient data stored on the electronic databases 106 and 120 mayinclude private and classified information, and it is desirable tomaintain a degree of confidentiality. The systems 100 and 130, and everysystem disclosed herein, are configured to comply with any privacy orconfidentiality laws that may exist in the jurisdiction in which thesystem is installed. In some implementations, all data in relation toall patients is processed using encryption and decryption algorithms toensure secure data transmission over the network 102.

FIG. 2 depicts a data structure 200 for records in a patient database,which may be stored in the electronic database 106. The data structure200 includes a list of patient identification numbers, representativeidentification numbers, and patient-related data, such as age, genderand the like. Upon registration, each patient may be labeled with apatient identification number, and in addition, the representative ofeach patient may also be labeled with a representative identificationnumber. For example, the representatives of the patients 1254 and 574may be legal guardians, physicians, pharmacists, or any other suitablerepresentative. In addition, a patient may be his/her ownrepresentative, as is the case with patient 1345.

The data structure 200 further includes the ages and genders of thepatients, and a flag variable representative of whether the patient isregistered. For registered patients, a date indicating the beginning ofthe administration of the drug and a date indicating the discontinuationof the drug administration are also recorded, if applicable. Forexample, the patients 1254 and 1345 were administered the drug for anamount of time before discontinuation, and the treatment of patient 576still includes the use of the drug. The patient 687 has not yet beenregistered, and so there is no corresponding representativeidentification number or dates of beginning and discontinuation of drugadministration.

The data structure 200 may also include further patient-relatedinformation, such as dates of actual administration of the drug, dosesof the administered drug, patient symptoms, or any other suitablepatient-related information. In particular, the data structure 200 maybe updated periodically with data generated from patient reports thatmay be prepared by the patient or a representative of the patient, or bythe health service provider. In this way, the data structure 200 maytrack the progression of a patient throughout the patient's treatment.By storing patient-related data in this way, the system 100 provides amethod for monitoring a patient's progress during treatment and alsoprovides a rich database with information that may provide insight forfuture decisions regarding the same patient or a patient with similarcharacteristics.

FIG. 3 is a flowchart of a method 300 that may be implemented by theserver 104 to authorize distribution of a drug for use in treating apatient. The method 300 includes the steps of receiving certificationthat a patient representative has received a warning of risks associatedwith use of a complement inhibitor (or a drug) and that therepresentative has agreed to use of the complement inhibitor for thepatient (step 350), storing data indicative of the certification in anelectronic database (step 352), and transmitting a signal indicative ofan authorization for distribution of the complement inhibitor (step354).

At step 350, the server 104 receives certification from a user device110 that a representative of a patient has received a warning regardingthe risks associated with the use of a complement inhibitor.Furthermore, the server 104 also receives certification that therepresentative has agreed to the use of the complement inhibitor intreatment for the patient. In particular, the representative may berequired to provide an acknowledgment of receipt of the warning as wellas agreement to use of the complement inhibitor in the form of asignature or any other suitable form of certification. Various types ofcertifications that can be used in the systems of the present inventionwould be readily apparent to one of ordinary skill in the art. Thiscertification may then be electronically acknowledged at a userinterface 114, and a signal representative of the certification may betransmitted over the network 102 and received by the server 104.

After receiving the certification, at step 352, the server 104 storesdata indicative of the certification in an electronic database 106. Forexample, a data structure such as data structure 200 or any othersuitable data structure may be stored in the electronic database 106 totrack the registration status of patients.

At step 354, the server 104 authorizes the distribution of thecomplement inhibitor by transmitting a signal over the network 104 tothe user device 110. The signal is indicative of the authorization touse the complement inhibitor in treating the registered patient. Thoseof ordinary skill will readily recognize that the authorization can takemany forms provided that they are suitable for use with the varioussystems of the present invention.

FIG. 4 is a flowchart of a method 400 that may be implemented by theserver 104 to receive and store patient-related data. The method 400includes the steps of receiving registered and authorized patient data(step 450), receiving a report of patient treatment (step 452), storingthe patient treatment in a database (step 454), receiving a report ofpatient symptoms (step 456), and storing the patient symptoms in thedatabase (step 458).

At step 450, the server 104 receives data related to a registeredpatient from a user device 110. For example, a user at the user device110 may wish to enter patient-related data into the electronic database106 and first provides selected data identifying the patient. Thereceived data may include the patient's identification number, such asdepicted in the first column of data structure 200, or any othersuitable data identifying the patient.

At step 452, the server 104 receives an electronic report of features ofa patient's treatment. The report may include information such as a drugthat was administered to the patient, the time and date ofadministration, and an amount of the administered drug. The report mayfurther include an identity of a person who administered the drug, wherethe administration took place, or any other selected information relatedto the treatment of the patient.

At step 454, the server 104 stores data corresponding to the receivedreport of patient treatment in the electronic database 106. In someimplementations, the processor 105 is configured to process the receivedreport before storage. For example, the information in the receivedreport may be sorted or categorized to facilitate efficient futureretrieval of the data.

At step 456, the server 104 receives a report of patient symptoms thatare determined during one or more subsequent treatment sessions orevaluations of the patient at the same or different health carefacility. The report may include quantitative measures such as thepatient's temperature, blood pressure, or any other suitablephysiological metric used to monitor a patient's overall health. Inaddition, the report may also include information such as aches,inflammation, irritation, discoloration, or any other suitable symptomidentified during that subsequent session. The symptom report may alsoinclude times or time intervals corresponding to each symptom.

At step 458, the patient symptoms are stored in the electronic database106. In some implementations, the processor 105 is configured to processthe received patient symptoms before storage. As an example, theinformation in the received patient symptom report may be processed tofacilitate efficient future retrieval of the data and to efficientlygroup a large number of patients together who exhibit similar symptoms.In particular, a quantitative measure such as the patient's temperaturemay be categorized as very high, high, normal, low, or very low, forexample.

FIG. 5 is a flowchart of a method 500 that may be implemented by theserver 104 to compare a symptom expressed by a patient with an adverseclinical event, such as an adverse event corresponding to a riskcertified previously by the patient or the patient's representative(e.g., FIG. 3). The method 500 includes the steps of storing a firstelectronic variable indicative of an acknowledged adverse clinical event(step 550) and storing a second electronic variable indicative of asymptom expressed by the patient (step 552). The first and secondelectronic variables are compared (step 554), and the processor 105determines whether there is a match between the two variables (step556). If a match is identified, then data indicative of the match isstored in the electronic database 106 (step 558), and a warning or otherindicator may be provided. A counter variable may be incremented thattracks a number of patients expressing a symptom that is not included asan adverse clinical event (step 560).

At step 550, the server 104 stores a first electronic variableindicative of an adverse clinical event acknowledged by the patient'srepresentative during patient registration. The first electronicvariable may be an identification number corresponding to the clinicalevent, or may simply be a flag variable indicating that the adverseclinical event has been acknowledged by the patient's representative.Other types of variables suitable for use with the systems of thepresent invention would be obvious to one of ordinary skill in the art.

At step 552, the server 104 stores a second electronic variableindicative of a symptom expressed by the patient. The second electronicvariable may be an identification number corresponding to the symptomand may have been received with the report of patient symptoms asdescribed in relation to FIG. 4. According to one practice, the reportof patient symptoms may have been processed to determine a value for thesecond electronic variable.

At step 554, the first and second electronic variables are compared. Theprocessor 105 may perform some processing on one or both of theelectronic variables in order to process, convert or otherwisemanipulate the variables into a form suitable for comparison.

At step 556, the server 104 determines whether there is a match betweenthe two electronic variables. In particular, a match requires that theexpressed symptom corresponds to the registered adverse clinical eventin some way. Furthermore, a match may be associated with a matchstrength value. According to one example, an adverse clinical eventassociated with a drug may be that the patient is susceptible to a risein temperature by a selected amount, for example, at least 5 degrees. Ifthe patient exhibits an increase in temperature greater than theselected amount (e.g., 6 degrees) after being administered the drug, theserver 104 may associate one match strength value with the patient. Ifanother patient exhibits an increase in temperature of 10 degrees afterbeing administered the drug, the server 104 may associated a strongermatch strength value with the other patient. These match strength valuesmay be also be stored in the electronic database 106 when updating thepatient's information. The match strength values can be pre-stored,pre-assigned or otherwise programmed in the system so that the processorcan determine or calculate a proper match strength value.

When the server 104 determines that a match has occurred, at step 557,the server 104 determines whether the drug was discontinued prior to theexpression of the symptom by the patient. In particular, if the drug wasdiscontinued prior to the expression of the symptom, at step 558, theserver 104 provides an alert to a user. The alert may includeinformation indicating that a match between a risk of a side effect thatwas acknowledged by the patient's representative and associated withdiscontinuing use of the drug and a symptom expressed by the patient hasoccurred. At step 559, the server 104 may store data indicative of thematch, such as the match strength value, or a flag variable indicatingthe match, in the electronic database 106 at step 558.

If the server 104 determines there is no match between the first andsecond electronic variables, at step 560, the server 104 may increment acounter variable. The counter variable corresponds to the expressedsymptom and represents a number of registered patients that haveexpressed the symptom during a predefined time interval afteradministration of the drug. The time interval may be a minute, an hour,a day, a week, or any other suitable time interval corresponding to anexpression of a symptom after drug administration. The server 104 maystore counter variables for a number of various symptoms not normallyassociated with the drug. The server 104 may also store separate countervariables for categories of patients, sorted by their age, gender, orany other suitable category for a patient. By incrementing these countervariables, the server 104 keeps track of a number of patients expressingparticular symptoms and can transmit an alert to an authorized user whenthe number of patients exceeds a predetermined threshold. In this way,the server 104 may detect symptoms that are often expressed by patientsin a particular category, in which the symptoms were not previouslyassociated with the drug.

Then, steps 552-560 may be repeated for each symptom retrieved from areceived symptom report for comparison to an adverse clinical event.Furthermore, method 500 may be repeated for each adverse clinical eventlisted in the warning received by the patient's representative forcomparison to each recorded symptom expressed by the patient.

FIG. 6 is a flowchart of a method 600 that may be implemented by theserver 104 to determine whether to authorize a user access to a selecteddrug (e.g., a complement inhibitor). The method 600 includes the stepsof receiving a user attempt to obtain access to a drug for a patient(step 650) and determining whether the patient is registered (step 652).If the patient is registered, the server 104 authorizes the user toobtain access to the drug (step 658). Otherwise, the user is prompted toregister the patient in the database (step 656). The patient may beregistered by the method described in FIG. 7.

FIG. 7 is a flowchart of a method 700 that may be implemented by theserver 104 to register a patient. The method 700 includes the steps ofconfirming an identity and a competency of a representative of thepatient (step 750), transmitting a warning to the patient representativeof risks associated with the drug (step 752), receiving acknowledgmentof the warning from the representative (step 754), receivingcertification that the representative agrees to the use of the drug intreating the patient (step 756), storing the patient in the database(step 758), and authorizing the distribution of the drug for treatingthe patient (step 760).

Using the above-described techniques, a complement-inhibitor-basedtreatment may be carried out. As noted above, thiscomplement-inhibitor-based treatment may entail an increased risk ofadverse events, such as meningococcal infections. Accordingly, thecomplement-inhibitor-based treatment may be combined with acomputer-implemented risk evaluation and mitigation strategy (REMS) anda safety and support program (SSP) to reduce the risk of adverse eventsand to effectively and quickly address an adverse event if one occurs.

Risk Evaluation and Mitigation Strategy (REMS)

The Risk Evaluation and Mitigation Strategy (REMS) may be used tomitigate the occurrence and morbidity associated with adverse eventssuch as meningococcal infections, and furthermore to educate health careproviders, patients, and caregivers regarding the increased risk ofadverse events, the early signs of adverse events, and the need forimmediate medical evaluation of signs and symptoms consistent withpossible occurrences of adverse events.

The REMS may involve certifying and/or registering qualified healthcareproviders that agree to abide by the REMS in a database. Prior toproviding the complement inhibitor for complement-inhibitor-basedtreatment, the database may be consulted to determine if the health careprovider is registered in the database. Registration in the database mayinvolve receiving certification from the health care provider that thehealth care provider will: counsel patients and provide patienteducational materials to the patient, provide a Medication Guide to thepatient prior to each infusion with the complement inhibitor, revieweducational materials and product labeling associated with thecomplement inhibitor and comply with the directions for safe use,including ensuring patients receive a meningococcal vaccine, including ameningococcal vaccine to Neisseria meningitidis serotype B, and promptlyreport adverse events, such as cases of meningococcal infection,including the patients' clinical outcomes.

A provider of the complement inhibitor may consult the database toverify that a prescriber requesting the complement inhibitor isregistered in the database. The provider may be prompted on apredetermined basis (e.g., once per year) to contact the prescribers inthe registry in order to provide educational materials to the registeredprescribers.

One important reason for implementing the REMS procedures is that earlyintervention in some kinds of adverse events, such as meningococcalinfections, is critical to successful outcomes. However, the nature oftreatment with a complement inhibitor may make it difficult to achieveearly intervention.

For example, the urgency required to treat a meningococcal infection maynecessitate treatment using different physicians than the originalprescriber of the complement inhibitor. Given that paroxysmal nocturnalhemoglobinuria and atypical hemolytic uremic syndrome (two conditionstreated by complement inhibitors, such as Soliris) are ultra-rare, thetreating health care provider may not be familiar with Soliris, and theincreased risk for infection in the patient, unless the patient informsthe health care provider. Furthermore, patients who are familiar withthe signs and symptoms of a meningococcal infection are more likely toseek out and receive early intervention which is known to lead to betteroutcomes.

FIG. 8 depicts exemplary components for implementing the REMS. The REMSmay make use of REMS Materials 802, which may include materials to bedistributed to patients and prescribers.

The REMS materials 802 may include a prescriber enrollment form 804. Theprescriber enrollment form 804 may be used to enroll prescribers in theREMS. In some embodiments, prescribers may submit a prescriberenrollment form 804 to a provider of a complement inhibitor prior toordering the complement inhibitor from the provider. Alternatively or inaddition, the prescriber may attempt to order the complement inhibitor,and the provider may inform the prescriber that the prescriber mustagree to enroll in the REMS program as a condition of the drug beingshipped. The prescriber enrollment form may be completed via telephone,facsimile, Internet, mail, electronic mail, or in person.

Prescribers of the complement inhibitor may be specially certifiedthrough the prescriber enrollment form 804. Certification may be basedon a prescriber agreement to counsel patients and provide to patientswith educational materials (listed below), to review these materials andcomply with directions for safe use, and to promptly report to thecomplement inhibitor provider and/or FDA serious life-threatening casesof adverse events, including meningococcal infections, and the outcomesof the adverse events. Prescribers may complete the prescriberenrollment form 804 to attest to this agreement.

The prescriber enrollment form 804 may include an agreement that theprescriber will undertake one or more selected actions. These actionsinclude a review of the product labeling and educational materials.These include a review of the Patient Safety Card 806, the MedicationGuide 808, the Patient Safety Information 810, the Prescriber SafetyInformation 812, the Prescribing Information 814, and the Dosing andAdministration Guide 816. The prescriber may also be required to performadditional actions, such as comply with safety instructions for useincluding ensuring patients are vaccinated with meningococcalvaccination, including meningococcal vaccination for Neisseriameningitidis serotype B; counsel patients and provide educationalmaterials to the patient; agree to promptly report cases ofmeningococcal infections and patient outcomes; and revaccinate accordingto current Advisory Committee on Immunization Practices medicalguidelines for vaccine use.

The Patient Safety Card 806 may also include directions for a treatingphysician (who may or may not be the physician that originallyprescribed the complement inhibitor), which calls to the physician'sattention the increased risk for the adverse event. The Patient SafetyCard 806 may include an instruction for the patient to carry the card atall times, and to show the card to a treating physician upon theoccurrence of an adverse event.

A Medication Guide 808 may also be provided to patients. The MedicationGuide 808 may be a brief educational document providing answers topatient questions about the complement inhibitor, possible side effectsand adverse events, and how and when the patient will receive thecomplement inhibitor. The Medication Guide 808 may include informationrequired to be communicated to a patient (e.g., by a regulatory agencysuch as the FDA).

The Medication Guide 808 may be packaged with every dose of thecomplement inhibitor. Furthermore, the Medication Guide 808 may beprovided to all prescribers for initial training along with othereducational material. Through the REMS enrollment process, eachprescriber may be asked to agree to dispense the Medication Guide 808 toeach patient at each infusion.

The REMS materials 802 may also include Patient Safety Information 810.The Patient Safety Information 810 represents educational materialsdesigned to be provided to the patient by the prescriber. The PatientSafety Information 810 may explain the information in the MedicationGuide 808 and may explain how to use the Patient Safety Card 806.Because the Medication Guide 808 may include regulatory information, apatient may better understand the information from the Medication Guide808 through the use of separate Patient Safety Information 810.

Particularly in the case of meningococcal infections, patient education(in addition to prescriber education) may be especially important. ThePatient Safety Card 806, Medication Guide 808, and Patient SafetyInformation 810 each provide opportunities to educate the patient andreinforce their understanding of the risk of adverse events.

One advantage of patient education through the combination of thePatient Safety Card 806, Medication Guide 808, and Patient SafetyInformation 810 is that the chance of early intervention in the case ofan adverse event is increased. Early intervention in the case ofmeningococcal infections is especially critical to successful outcomes.The urgency required to treat a meningococcal infection may necessitatetreatment using different physicians. Given that paroxysmal nocturnalhemoglobinuria and atypical hemolytic uremic syndrome (two conditionstreated by complement inhibitors, such as Soliris) are ultra-rare, thetreating health care provider may not be familiar with Soliris, and theincreased risk for infection in the patient, unless the patient informsthe health care provider. Furthermore, patients who are familiar withthe signs and symptoms of a meningococcal infection are more likely toseek out and receive early intervention which is known to lead to betteroutcomes.

The REMS materials 802 may further include Prescribing SafetyInformation 812. The Prescribing Safety Information may include anexplanation to a prescriber as to how to explain the Patient Safety Card806 and the Mediation Guide 808 to patients. By providing multipledifferent sources of consistent information (e.g., the Medication Guide808 from the complement inhibitor provider and the Prescribing SafetyInformation 812 from the prescriber), the patient's understanding of thesafety information contained in the REMS materials 802 may be increased.

The REMS materials 802 may further include Prescribing Information 814.The Prescribing Information 814 may provide, for the prescriber, adetailed overview of the complement inhibitor, conditions treated by thecomplement inhibitor, mechanisms of action, warnings and precautions,possible adverse events associated with the complement inhibitor, andother information needed to prescribe and use the complement inhibitorsafely and effectively. The Prescribing Information 814 may includeinformation required by regulatory agencies, such as the FDA.

A Dosing and Administration Guide 816 may also be provided. The Dosingand Administration Guide 816 may serve as a reference for the prescriberas to how to properly administer the complement inhibitor to a patient.

The REMS materials may also include a Patient Voluntary Enrollment Form818. The Patient Voluntary Enrollment Form 818 may allow a patient toenroll, if desired, in the Safety and Support Program (SSP). The PatientVoluntary Enrollment Form 818 may provide patients with ways to discussthe educational material with a Nurse Case Manager through the SSP. Thepatient may be given the opportunity to ask any questions that he/shemay have and to enroll in the SSP program. Enrolling in the SSP programprovides an extra point of contact with the patient (in this case,between the patient and the provider of the complement inhibitor) inorder to further reinforce the patient's understanding of thepossibility of adverse events.

The REMS materials 802 may optionally include Surveys 820. In someembodiments, a provider of the complement inhibitor may conduct surveysof prescribers and/or patients at predetermined intervals (e.g., everytwo years). The Surveys 820 may be used to assess prescriber and patientunderstanding of the REMS educational materials which communicateimportant safety information associated with complement-inhibitor-basedtreatment and meningococcal infection risk, as well as steps that can betaken to minimize the risks. In the Surveys 820, participants may beasked to indicate which educational materials have been read orreferenced over the survey period and how recently the surveyparticipant consulted these materials over the past year.

When the survey 820 is directed to a prescriber, the survey may containa series of questions to gauge understanding of the key REMS concepts,including but not limited to the risk of meningococcal infection; theneed for meningococcal vaccinations and revaccinations, includingmeningococcal vaccination for Neisseria meningitidis serotype B; theneed to educate patients regarding the use of the Patient Safety Card806: the need for continuous reinforcement of the risks associated withcomplement-inhibitor-based treatment; and/or what to do in the event ofan infection.

When the survey 820 is directed to a patient, the survey may contain aseries of questions to gauge his/her understanding of the key REMSconcepts, including but not limited to the risk of meningococcalinfection; the need for meningococcal vaccinations and revaccinations,including meningococcal vaccination for Neisseria meningitidis serotypeB; the use of the Patient Safety Card 806; the warning signs of ameningococcal infection; and/or what to do in the event of infection.

A REMS Software Tool 822 may enforce protocols of the REMS, ensureongoing prescriber and patient education, and assist in the detectionand reporting of adverse events. The REMS software tool 822 may beprogrammed with the dates, time intervals, and actions to be taken inaccordance with the REMS. Exemplary procedures that may be carried outby the REMS Software Tool 822 are described in more detail with respectto FIG. 9A and FIG. 9B.

To ensure that the complement inhibitor is distributed only to certifiedprescribers, the REMS Software Tool 822 may maintain a database ofcertified prescribers in the REMS program. Additionally, the REMSSoftware Tool 822 may generate regular prompts to verify thatprescribers comply with requirements of the REMS Program.

Safety Support Program

A Safety Support Program (SSP) may complement and reinforce the REMS.The SSP provides education as well as disease and treatment support forpatients who have been enrolled in a complement-inhibitor-basedtreatment plan. The SSP provides additional procedures beyond thosedefined in the REMS to further mitigate the risk of seriousmeningococcal infection in patients being treated with complementinhibitors. The SSP concentrates on counseling the patient, training(e.g., need for vaccination; risks of developing meningococcal and otherserious infections; and the risk of developing serious hemolysisfollowing complement inhibitor discontinuation with continued monitoringafter discontinuation), enrollment, documentation, and safetyevaluation. Examples of activities performed in the SSP include: eachpatient may be assigned a professional nurse personal contact to serveas their Nurse Case Manager; calls made at predetermined periods of time(e.g., monthly) to patients by the Nurse Case Managers as allowed by thepatient to ensure that they have a copy of the Patient Safety Card 804and to review signs and symptoms of meningococcal infection; patientvaccination dates are monitored and a revaccination reminder letter ismailed to the prescriber or patient in advance of each patient's 3-yearvaccination anniversary date; patients are encouraged to voluntarilyreport adverse events to their Nurse Case Manager; and patients areencouraged to contact their Nurse Case Manager with any questions abouttheir treatment.

With reference again to FIG. 8, a patient safety registry 826 may bemaintained as part of the SPP. The patient safety registry may includepatients who have voluntarily signed up for the SPP and who wish toreceive reminders and educational materials regarding treatment with thecomplement inhibitor. Patients may be enrolled in the SSP and may beentered into the patient safety registry upon receipt of the patientvoluntary enrollment form 818 from the REMS materials 802.

A Baseline Data Form may be completed for each voluntarily enrolledpatient in the patient safety registry 826 within 30 days of initiatingcomplement-inhibitor-based treatment. The Baseline Data Form may be usedto collect information regarding patient demographics, past medicalhistory and current medical condition, and vaccination status.

An SSP software tool 828 may enforce protocols of the SSP, for example,by prompting a Registered Nurse Care Manager assigned to a patient toperform one or more of the above-identified actions. The SSP softwaretool 828 may be programmed with the dates, time intervals, and actionsto be taken in accordance with the SSP. Exemplary procedures that may becarried out by the SSP Software Tool 828 are depicted in FIG. 9B andFIG. 9C.

The SSP may be staffed by Registered Nurse Case Managers who can addressquestions related to disease and treatment, perform a consultation atany time, and provide tools that help patients track and manage theirdisease. It is very important to realize that a meningococcal infectionis an acute disease and can progress to death or permanent disabilitywithin a day. The availability of a Nurse Case Manager is particularlyuseful because the symptoms of early meningococcal infection are diverseand not every patient has the same set of presenting symptoms. Inaddition, the symptoms are not unique to meningococcal infection and mayseem like flu, gastroenteritis or even a hangover. Symptoms includefever, cold hands and feet, sore muscles, sore joints, nausea, vomiting,stiff neck, painful neck, backache, sore throat, lack of energy anddifferent combinations of symptoms may present during a given episode.When a patient who is participating in a patient safety support programexperiences any sort of symptom, they may call their Nurse Case Managerwho understands the diversity of possible symptoms may direct them toimmediately seek treatment for possible meningococcal infection in theform of antibiotics.

Nurse Case Managers also put patients in touch with other patientssuffering from the same conditions when requested to do so. To this end,the SSP software tool may access a registered nurse registry 830, whichmay be a database identifying registered nurses who have agreed toparticipate in the SSP. In some embodiments, all activities of the SSPmay be performed by a Registered Nurse Case Manager.

Exemplary procedures performed by the REMS software tool 822 and the SPPsoftware tool 828 are next described with reference to FIGS. 9A-9C.

Exemplary Method for Implementing REMS and SSP

FIG. 9A depicts an exemplary procedure for enrolling a prescriber in theREMS. At step 902, a provider of a complement inhibitor may receive anenrollment request from a prescriber or other health care professional(HCP). The enrollment request may request that the provider enroll theprescriber/HCP in the REMS/SSP program. The enrollment request mayoptionally request that the provider send the complement inhibitor tothe prescriber. The enrollment request may be in the form, for example,of the Prescriber Enrollment Form 804. The enrollment request may beelectronically submitted, in which case it may be received and processedby the REMS software tool 822. If the enrollment request is notelectronically submitted (e.g., the enrollment request is submitted byphone, mail, or in person), then information from the enrollment requestmay be entered into the REMS software tool 822 by the recipient of theenrollment request.

The REMS software tool 822 may create an entry associated with therequesting prescriber/HCP. For example, the REMS software tool 822 maycreate a new entry in the Prescriber Registry 824, or may temporarilystore information about the requesting prescriber/HCP in memory until ithas been verified that the prescriber/HCP has agreed to abide by all ofthe requirements of the REMS and/or SSP.

At step 904, it may be determined whether the requester has agreed tovaccination and/or revaccination requirements for the complementinhibitor. For example, the Prescriber Enrollment Form 804 may include arequirement that the prescriber/HCP agrees to vaccinate (or havevaccinated) any patients receiving the complement inhibitor according toa predetermined time requirement (e.g., vaccination must occur at leasttwo weeks prior to administering the complement inhibitor). ThePrescriber Enrollment Form 804 may also require that the prescriber/HCPagrees to revaccinate the patient at predetermined intervals (e.g.,every three years for a meningococcal vaccination) and/or agrees toeducate the patient regarding the ongoing need for revaccination. Theprescriber may indicate their agreement to the vaccination/revaccinationrequirements (or any other requirement) through an initial or checkmarkon a vaccination-specific portion of the Prescriber Enrollment Form 804,by signing a general agreement to abide by all of the requirements onthe Prescriber Enrollment Form 804, through an oral agreement, orthrough other means showing an active, affirmative agreement to abide bythe vaccination/revaccination requirements.

If the answer at step 904 is “NO” (i.e., the prescriber has not agreedto the vaccination/revaccination requirements), then the REMS softwaretool 822 may, at step 906, set a vaccination flag associated with theprescriber entry created in step 902 to “NO” or “FALSE.” The REMSsoftware tool 822 may indicate that the prescriber/HCP cannot becertified in the Prescriber Registry 824 until the prescriber/HCP hasagreed to the vaccination/revaccination requirements, and may flag theprescriber/HCP for follow up by the provider of the complementinhibitor. If the answer at step 904 is “YES,” then at step 908 the REMSsoftware tool 822 may set the vaccination flag to “YES” or “TRUE.”

Additional requirements of the REMS/SSP are addressed in steps 910, 914,and 918. Optionally, even if the answer at step 904 is “NO,” processingmay continue to steps 910, 914, and 918 so that each missing requirementcan be flagged to the prescriber/HCP at the same time. If the enrollmentrequest was received electronically at step 902, the REMS software tool822 may automatically respond to the request by transmitting anindication of any or all missing requirements to the prescriber/HCP.

At step 910, it may be determined whether the requester has agreed toeducation requirements for the complement inhibitor. For example, thePrescriber Enrollment Form 804 may include a requirement that theprescriber/HCP agrees to counsel patients, caregivers, and/or legalguardians and provide educational materials to the patients, caregivers,or legal guardians. Such educational materials may include the PatientSafety Card 806 and/or the Medication Guide 808. If the answer at step910 is “NO” (i.e., the prescriber has not agreed to the educationrequirements), then the REMS software tool 822 may set an education flagassociated with the prescriber entry created at step 902 to “NO” or“FALSE.” The REMS software tool 822 may indicate that the prescriber/HCPcannot be certified in the Prescriber Registry 824 until theprescriber/HCP has agreed to the education requirements, and may returnto step 906 to flag the prescriber/HCP for follow up by the provider ofthe complement inhibitor. If the answer at step 910 is “YES,” then atstep 912 the REMS software tool 822 may set the education flag to “YES”or “TRUE.”

At step 914, it may be determined whether the requester has agreed toreporting requirements relating to adverse events associated with thecomplement inhibitor. For example, the Prescriber Enrollment Form 804may include a requirement that the prescriber/HCP agrees to promptlyreport cases of specified adverse events (such as meningococcalinfections, other infections caused by encapsulated bacteria, generallyinfections, and hemolysis) to the provider and/or a regulatory agencysuch as the FDA. If the answer at step 914 is “NO” (i.e., the prescriberhas not agreed to the reporting requirements), then the REMS softwaretool 822 may set a reporting flag associated with the prescriber entrycreated at step 902 to “NO” or “FALSE.” The REMS software tool 822 mayindicate that the prescriber/HCP cannot be certified in the PrescriberRegistry 824 until the prescriber/HCP has agreed to the reportingrequirements, and may return to step 906 to flag the prescriber/HCP forfollow up by the provider of the complement inhibitor. If the answer atstep 914 is “YES,” then at step 916 the REMS software tool 822 may setthe reporting flag to “YES” or “TRUE.”

At step 918, it may be determined whether the requester has agreed toadministration requirements relating to adverse events associated withthe complement inhibitor. For example, the Prescriber Enrollment Form804 may include a requirement that the prescriber/HCP agrees to reviewproduct labeling and prescriber educational materials (such as any orall of the Prescriber Safety Information 812, Prescribing Information814, and Dosing and Administration Guide 816), and to administer thecomplement inhibitor in accordance with the product labeling and theprescriber educational materials. If the answer at step 918 is “NO”(i.e., the prescriber has not agreed to the administrationrequirements), then the REMS software tool 822 may set a reporting flagassociated with the prescriber entry created at step 902 to “NO” or“FALSE.” The REMS software tool 822 may indicate that the prescriber/HCPcannot be certified in the Prescriber Registry 824 until theprescriber/HCP has agreed to the administration requirements, and mayreturn to step 906 to flag the prescriber/HCP for follow up by theprovider of the complement inhibitor. If the answer at step 918 is“YES,” then at step 920 the REMS software tool 822 may set theadministration flag to “YES” or “TRUE.”

At step 922, the REMS software tool 822 may determine if each of theflags (vaccination, education, reporting, and administration) have beenset to “YES” or “TRUE.” If the prescriber/HCP has agreed to each ofthese requirements, then the REMS software tool 822 may add theprescriber/HCP to the Prescriber Registry 824. At that point, theprescriber may be considered as certified to prescribe the complementinhibitor.

It is noted that the procedure depicted in FIG. 9A is exemplary only.For example, the vaccination flag, the education flag, the reportingflag, and the administration flag may all be combined into one flag(e.g., a single flag indicating that the prescriber has agreed to allrelevant conditions). Alternatively, these flags may be implicit in theentry of a prescriber into the prescriber database (i.e., if aprescriber is present in the database, this may be taken to mean thatthe prescriber has agreed to all relevant conditions).

FIG. 9B depicts an exemplary procedure for issuing a complementinhibitor to a requesting prescriber and following up with therequesting prescriber according to the REMS/SSP. At step 924, a providerof a complement inhibitor may receive a requisition request from aprescriber/HCP. The requisition request may request that the providersend a specified number of vials or doses to the prescriber/HCP. Therequisition request may be electronically submitted, in which case itmay be received and processed by the REMS software tool 822. If therequisition request is not electronically submitted (e.g., therequisition request is submitted by phone, mail, or in person), theninformation from the requisite request may be entered into the REMSsoftware tool 822 by the recipient of the requisition request.

At step 926, the REMS software tool 822 may be used to inspect thePrescriber Registry 824. The REMS software tool 822 may access thePrescriber Registry 824, either locally (e.g., by consulting a databasestored in memory on the same machine as the REMS software tool 822) orremotely (e.g., by using a network connection and/or remote databaseprocedure calls to retrieve information from a database stored on amachine remote from the REMS software tool 822).

At step 928, the REMS software tool 822 may determine whether theprescriber/HCP was located in the Prescriber Registry 824. In someembodiments, the presence of the prescriber/HCP in the PrescriberRegistry 824 may be sufficient to indicate that the prescriber iscertified to provide the complement inhibitor. In other embodiments, ifthe Prescriber Registry 824 includes flags (such as the above-describedvaccination flag, education flag, reporting flag, and administrationflag) or other indicia of suitability for receiving the complementinhibitor, the REMS software tool 822 may verify that all or asufficient number (as may be determined based on the application) offlags or indicia are set to appropriate values in order to certify theprescriber/HCP. If the answer at step 928 is “NO,” then theprescriber/HCP is not certified to provide the complement inhibitor.Accordingly, at step 930, the REMS software tool 822 may report that theprescriber/HCP is not authorized to receive the complement inhibitor.Optionally, the REMS software tool 822 may automatically transmit amessage describing any requirements not met by the prescriber/HCP, andincluding some or all of the REMS materials 802. If the answer at step928 is “YES,” then at step 932 the REMS software tool 822 may authorizesending the complement inhibitor to the prescriber/HCP. The REMSsoftware tool 822 may add one or more follow-up dates to theprescriber/HCP's entry in the Prescriber Registry 824. For example, thefollow-up dates may include dates on which the prescriber/HCP should becontacted to determine whether the prescriber/HCP is aware of anyadverse conditions that have not yet been reported to the provider,dates on which the prescriber/HCP should be provided with additional ornew copies of educational materials, and dates on which theprescriber/HCP and/or the prescriber/HCP's patient should be providedwith surveys.

At step 934, when the REMS software tool 822 identifies that anadverse-condition follow up date has arrived, the REMS software tool 822may prompt the provider to contact the prescriber/HCP to determinewhether any unreported adverse events have occurred. The follow-up ofstep 934 may occur at predetermined times or intervals, such as on amonthly or annual basis, or after a predetermined amount of time afterthe prescriber requests the complement inhibitor. Any adverse eventsincluding adverse events originally reported by the prescriber/HCP andadverse events discovered during the follow-up of step 934 may betracked in the REMS software tool 822 for completeness and to monitoroutcome, especially serious infections, using a standard data gatheringapproach to identify the likely cause of the infection and otherfeatures of the adverse event. One or more attempts may be made by theprovider to obtain follow-up information. The REMS software tool 822 maygenerate and present individual meningococcal reports and may conduct amonthly and/or quarterly signal detection process which reviews adverseevents reported worldwide. One possibility at step 934 (among othersteps in FIGS. 9A-9C) is that the prescriber may indicate that thepatient has been “lost to follow up” (i.e. the prescriber has notfollowed up with the patient due to for example an inability to locatethe patient). Due diligence may be performed to follow-up patientsreported by the HCP as lost to follow up. If the patient is eventuallycontacted and it is discovered that the patient has switched to adifferent HCP, the patient's new prescriber may be checked against theprescriber database to verify if the current prescriber is enrolled inthe REMS/SSP program. If not, the provider may send the REMS materials802 to the new prescriber and request that the prescriber enroll in theREMS/SSP program. Alternatively, if the patient indicates that treatmenthas been discontinued, the last date of complement inhibitor treatmentmay be entered into the Patient Safety Registry 826, as well asinformation provided by the prescriber/HCP related to follow-up aftercomplement inhibitor discontinuation.

At step 936, when the REMS software tool 822 identifies that aneducation material update date has arrived, the REMS software tool 822may prompt the provider to contact the prescriber/HCP to provide theprescriber/HCP with updated copies of the REMS materials 802, if any ofthe materials have been updated, and/or copies of documents such as thePrescriber Safety Information 812, the Prescribing Information 814, andthe Dosing and Administration Guide 816. The follow-up of step 936 mayoccur at predetermined times or intervals, such as on an annual basis,or after a predetermined amount of time after the prescriber requeststhe complement inhibitor, or at any time in which the educationalmaterials are updated. The purpose of this outreach is to remindprescribers of the REMS program and emphasize the need for safe use ofcomplement inhibitors. The REMS software tool 822 may prompt theprovider to review and discuss with the prescribers the educationalmaterial previously provided and update them on any new data availableto the provider.

At step 938, the provider of the complement inhibitor may be prompted,on a predetermined basis, to send surveys 820 to the prescribers in thePrescriber Registry 824 and/or patients in the Patient Safety Registry826. The surveys may assess compliance with vaccination requirements aswell as knowledge of the risks of complement inhibitor treatment and theneed for vaccination. In addition to providing information to theprovider regarding patient and prescriber compliance with the REMS/SSPrequirements, the surveys 820 provide an additional opportunity toreinforce the requirements and present them to the prescriber/patient ina different format.

FIG. 9C depicts an exemplary procedure for enrolling a patient in theSSP. At step 940, the SPP software tool 828 may decide whether to enrolla patient in the SPP. For example, the SPP software tool 828 may enrolla patient in the SPP upon receiving an enrollment request, such as thePatient Voluntary Enrollment Form 818. The enrollment request may beelectronically submitted, in which case it may be received and processedby the SPP software tool 828. If the enrollment request is notelectronically submitted (e.g., the enrollment request is submitted byphone, mail, or in person), then information from the enrollment requestmay be entered into the SPP software tool 828 by the recipient of theenrollment request.

Upon receiving the enrollment request, the SPP software tool 828 may addinformation from the Patient Voluntary Enrollment Form 818 to thePatient Safety Registry 826. The information may be contained on thePatient Voluntary Enrollment Form 818, or may be contained in asubsequently-received document (e.g., the Baseline Data Form mentionedabove). If the SPP software tool 828 determines that the patient'srecords are incomplete (e.g., if some of the patient's demographic dataand/or dates of vaccination are not present), the SPP software tool 828may request additional information from the patient (e.g., byautomatically transmitting the Baseline Data Form to the patient, or byprompting the provider to do so).

If the answer at step 940 is “YES” (i.e., the patient should be enrolledin the SPP), then at step 942 the provider may be prompted on apredetermined basis (e.g., after a predetermined amount of timefollowing an event, such as the start of treatment, the stoppage oftreatment, or the occurrence of an adverse event) to follow up with thepatients in the Patient Safety Registry 828. The Patient Safety Registry828 may further be analyzed at predetermined intervals in order todetermine patients at an increased risk of adverse events. Such patientsmay be flagged for further follow-up. The follow-ups may involve datacollection beyond routine pharmacovigilance, including monitoring forearly signs of meningococcal infection or other adverse events coupledwith immediate evaluation of suspected infection followed by antibiotictreatment if necessary. Furthermore, the follow-ups may involve aspecial pharmacovigilance effort to actively monitor and collectlong-term patient data pertinent to treatment with the complementinhibitor and known adverse events related to the complement inhibitor.

Regardless of whether the patient is enrolled in the SPP at step 940, atstep 944, the SPP software tool 828 may prompt the provider to provide avaccination reminder 944. If the patient was enrolled in the SPP at step940, then the SPP software tool 828 may access the Patient SafetyRegistry 826 to identify the most recent date of vaccination for theclient. The SPP software tool 828 may then calculate, based on arecommended amount of time between vaccinations, when to send arevaccination reminder to the patient (or when to prompt the provider tosend the revaccination reminder). For example, the SPP software tool 828may send the reminder (or prompt for the reminder to be sent) by apredetermined amount of time (e.g., two months) before revaccination isdue. If the patient was not enrolled in the SPP at step 940, then theSPP software tool 828 may send revaccination reminders toprescribers/HCPs at predetermined times. The predetermined times may bea predetermined amount of time after the prescriber/HCP reports that avaccination or complement-inhibitor treatment was first administered, ormay be a general reminder to have their patients revaccinated issued atpredetermined intervals (e.g., once per year).

A REMS and SSP plan was carried out according to the above-describedembodiments from 2007-2014. FIG. 10 is a graph showing rates ofpost-marketing meningococcal infections per 100,000 persons, by year,for patients exposed to a C5 complement inhibitor (Soliris®) followingFDA approval of the complement inhibitor. As can be seen in the graph ofFIG. 10, the rate of meningococcal infections showed a strong downwardtrend in the years following the implementation of the REMS/SSP (thesharp increase in the Ex-US rate observed in 2014 is attributed to thelaunch of Soliris® in new countries such as Greece). The meningococcalinfection rate reported in patients with PNH immediately followingmarket approval of Soliris was consistent with expectations based on themedical literature available for infection rates in individuals withknown terminal complement mutations. Since full implementation of theREMS, a steady trend of a decreasing post-marketing meningococcalinfection rate over time has been observed. Furthermore, US rates arelower compared to Ex-US rates, and the inventors believe that the REMSprogram is an important reason for this difference. All together, thisdata supports the success of the REMS in meeting its primary goal ofmitigating the occurrence and morbidity associated with meningococcalinfections.

Since the FDA's approval in 2007 of Soliris for the treatment ofpatients with PNH, a total of 15 post-marketing cases of meningococcalinfections have been reported corresponding to a rate of 268.1 cases per100,000 person years. Vaccination history was confirmed in all reportedcases. Of the 15 cases, there was only 1 fatality. One reported case ofinvasive meningococcal infection is resolving; all remaining cases haveresolved.

The rate of mortality from meningococcal infection in the general U.S.population was 2 per 15 cases (CDC 2013). The lower rate (1 per 15cases) observed in the Soliris-treated post-marketing populationstrongly demonstrates the effectiveness of the REMS program, with thesupport of the SSP, despite the fact that Soliris-treated patientsrepresent a sicker population than the general population. By the natureof their disease, patients with PNH and aHUS (two conditions treated bySoliris) might be expected to be at a higher risk for meningococcalinfections, but the data indicates that patients receiving Soliris havea lower risk of meningococcal infection compared with individuals withLCCD. The annual number of reported post-marketing cases inSoliris-treated patients with PNH or aHUS has consistently been between1-2, with the exception of 4 cases reported in 2011 (all in patientswith PNH), despite an increase in exposure over time as more patientscome on treatment or remain on treatment.

The inventors believe that this trend is attributable to the REMSprogram and the reinforcement of key safety messages provided by theSSP. Among other factors, strong patient knowledge regarding the needfor meningococcal vaccinations and actions to take if symptoms suggestthe possibility of meningococcal infection plays a significant role inmitigating the risk of meningococcal infection and its outcomes. Throughthe prescriber and patient education components of the REMS, and theadditional activities of the SSP, these patients are in regular contactwith a Nurse Case Manager and receive ongoing reinforcement of thesafety messages related to Soliris treatment. The survey data availablefrom these patients supports and illustrates the success andeffectiveness of the REMS tools in educating patients. Further, theavailable evidence supports and illustrates the success of the REMS andSSP programs to prevent the occurrence of meningococcal infection inthis at-risk population through the consistent education of both HCPsand their patients.

Those of ordinary skill in the art will readily recognize that one ormore of the foregoing notifications, prompts, actions, dissemination ofsurveys, and the like can be performed automatically by one or more ofthe computer device or processor and/or by the one or more of the REMSsoftware tool 822 and the SSP software tool 828.

The above-described steps may be performed in hardware logic, softwarelogic, or a combination of hardware and software logic. FIG. 11 is ablock diagram of a computing or electronic device, such as any of thecomponents of the systems illustrated in FIGS. 1A-1B, and which aresuitable for performing any of the processes described herein. Each ofthe components of these systems may be implemented on one or morecomputing devices 1100. In certain aspects, a plurality of thecomponents of these systems may be included within one computing device1100. In certain implementations, a component and a storage device maybe implemented across several computing devices 1100.

The computing device 1100 comprises at least one communicationsinterface unit, an input/output controller 1110, system memory, and oneor more data storage devices. The system memory includes at least onerandom access memory (RAM) 1102 and at least one read-only memory (ROM)1104. All of these elements are in communication with a centralprocessing unit (CPU) 1106 to facilitate the operation of the computingdevice 1100. The computing device 1100 may be configured in manydifferent ways. For example, the computing device 1100 may be aconventional standalone computer or alternatively, the functions ofcomputing device 1100 may be distributed across multiple computersystems and architectures. In FIG. 11, the computing device 1100 islinked, via a network or a local network, to other servers or systems.

The computing device 1100 may be configured in a distributedarchitecture, wherein databases and processors are housed in separateunits or locations. Some units perform primary processing functions andcontain at a minimum a general controller or a processor and a systemmemory. In distributed architecture implementations, each of these unitsmay be attached via the communications interface unit 1108 to acommunications hub or port (not shown) that serves as a primarycommunication link with other servers, client or user computers andother related devices. The communications hub or port may have minimalprocessing capability itself, serving primarily as a communicationsrouter. A variety of communications protocols may be part of the system,including, but not limited to: Ethernet, SAP, SAS™, ATP, BLUETOOTH™, GSMand TCP/IP.

The CPU 1106 comprises a processor, such as one or more conventionalmicroprocessors and if desired one or more supplementary co-processorssuch as math co-processors for offloading workload from the CPU 1106.The CPU 1106 is in communication with the communications interface unit1108 and the input/output controller 1110, through which the CPU 1106communicates with other devices such as other servers, user terminals,or devices. The communications interface unit 1108 and the input/outputcontroller 1110 may include multiple communication channels forsimultaneous communication with, for example, other processors, serversor client terminals.

The CPU 1106 is also in communication with the data storage device. Thedata storage device may comprise an appropriate combination of magnetic,optical or semiconductor memory, and may include, for example, RAM 1102,ROM 1104, flash drive, and an optical disc such as a compact disc or ahard disk or drive. The CPU 1106 and the data storage device each maybe, for example, located entirely within a single computer or othercomputing device or connected to each other by a communication medium,such as a USB port, serial port cable, a coaxial cable, an Ethernetcable, a telephone line, a radio frequency transceiver or other similarwireless or wired medium or combination of the foregoing. For example,the CPU 1106 may be connected to the data storage device via thecommunications interface unit 808. The CPU 1106 may be configured toperform one or more particular processing functions.

The data storage device may store, for example, (i) an operating system1112 for the computing device 1100; (ii) one or more applications 1114(e.g., computer program code or a computer program product) adapted todirect the CPU 1106 in accordance with the systems and methods describedhere, and particularly in accordance with the processes described indetail with regard to the CPU 1106; or (iii) database(s) 1116 adapted tostore information that may be utilized to store information required bythe program.

The operating system 1112 and applications 1114 may be stored, forexample, in a compressed, an uncompiled and/or an encrypted format, andmay include computer program code. The instructions of the program maybe read into a main memory of the processor from a computer-readablemedium other than the data storage device, such as from the ROM 1104 orfrom the RAM 1102. While execution of sequences of instructions in theprogram causes the CPU 1106 to perform the process steps describedherein, hard-wired circuitry may be used in place of, or in combinationwith, software instructions for implementation of the processes of thepresent disclosure. Thus, the systems and methods described are notlimited to any specific combination of hardware and software.

Suitable computer program code may be provided for performing one ormore functions in relation to aligning dietary behavior as describedherein. The program also may include program elements such as anoperating system 1112, a database management system and “device drivers”that allow the processor to interface with computer peripheral devices(e.g., a video display, a keyboard, a computer mouse, etc.) via theinput/output controller 1110.

The term “computer-readable medium” as used herein refers to anynon-transitory medium that provides or participates in providinginstructions to the processor of the computing device 1100 (or any otherprocessor of a device described herein) for execution. Such a medium maytake many forms, including but not limited to, non-volatile media andvolatile media. Non-volatile media include, for example, optical,magnetic, or opto-magnetic disks, or integrated circuit memory, such asflash memory. Volatile media include dynamic random access memory(DRAM), which typically constitutes the main memory. Common forms ofcomputer-readable media include, for example, a floppy disk, a flexibledisk, hard disk, magnetic tape, any other magnetic medium, a CD-ROM,DVD, any other optical medium, punch cards, paper tape, any otherphysical medium with patterns of holes, a RAM, a PROM, an EPROM orEEPROM (electronically erasable programmable read-only memory), aFLASH-EEPROM, any other memory chip or cartridge, or any othernon-transitory medium from which a computer can read.

Various forms of computer readable media may be involved in carrying oneor more sequences of one or more instructions to the CPU 1106 (or anyother processor of a device described herein) for execution. Forexample, the instructions may initially be borne on a magnetic disk of aremote computer (not shown). The remote computer can load theinstructions into its dynamic memory and send the instructions over anEthernet connection, cable line, or even telephone line using a modem. Acommunications device local to a computing device 1100 (e.g., a server)can receive the data on the respective communications line and place thedata on a system bus for the processor. The system bus carries the datato main memory, from which the processor retrieves and executes theinstructions. The instructions received by main memory may optionally bestored in memory either before or after execution by the processor. Inaddition, instructions may be received via a communication port aselectrical, electromagnetic or optical signals, which are exemplaryforms of wireless communications or data streams that carry varioustypes of information. The computer readable medium can be part of acomputer device, with a processor that can process the medium.

All references cited herein, including patent applications andpublications, are hereby incorporated by reference in their entirety.Various modifications of the disclosure, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims.

What is claimed is:
 1. A method, comprising: receiving a request from aprescriber to distribute a complement inhibitor; verifying that theprescriber has agreed to the following conditions: (a) to vaccinatepatients with a Neisseria meningococcal type B specific vaccine, and/orrevaccinate patients according to a pre-determined schedule with aNeisseria meningococcal type B specific vaccine at predetermined timesor intervals, (b) to provide the patients with educational materialsregarding the complement inhibitor, and (c) that the prescriber hasreviewed information relating to administering the complement inhibitor;accessing, using a computer with a processor programmed to perform theaccessing, a database of certified prescribers; adding, using theprocessor, the prescriber to the database of certified prescribers, theadding performed only if the prescriber has agreed to conditions (a)-(c)in order to counsel the patient with regard to the risks associated withthe complement inhibitor and is vaccinated or revaccinated to prevent ameningococcal infection, and that the prescriber is educated with regardto administering the complement inhibitor to the patient; receiving arequisition from the prescriber, the requisition requesting that theprescriber be provided with the complement inhibitor; inspecting, usingthe processor, the database of certified prescribers; and authorizing,using the processor, the prescriber to receive the complement inhibitoronly if the prescriber is in the database of certified prescribers. 2.The method of claim 1, wherein an entry in the database associated withthe prescriber is associated with one or more flags certifying that theprescriber has agreed to comply with conditions (a)-(c); and theprescriber is only authorized to receive the complement inhibitor if theone or more flags indicate that the prescriber has agreed to comply withconditions (a)-(c).
 3. The method of claim 1, further comprisingprompting, after a predetermined period of time, a reminder to follow upwith the prescriber as to whether the prescriber is aware of an adverseevent associated with providing the complement inhibitor to the patient;and upon prompting, the computer comprises an interface and generates areminder to send to the prescriber.
 4. The method of claim 3, whereinthe adverse event is an infection caused by a meningococcal bacteria. 5.The method of claim 3, wherein the adverse event is hemolysis.
 6. Themethod of claim 1, further comprising prompting, after a predeterminedperiod of time, a reminder to provide the prescriber existing or updatededucational materials about the complement inhibitor; and an interfaceto send the reminder to the prescriber.
 7. The method of claim 1,further comprising transmitting, after a predetermined period of time, asurvey regarding the prescriber's compliance with one or more ofconditions (a)-(c).
 8. The method of claim 1, further comprisingreceiving a report from the prescriber that a patient was lost to followup; identifying a new prescriber associated with the patient; andperforming at least one of the following: verifying that the newprescriber is in the database of certified prescribers, or verifyingthat the patient is no longer being treated with the complementinhibitor, and triggering a post-treatment reminder to follow up withthe patient regarding the occurrence of any adverse events followingdiscontinuation of the complement inhibitor.
 9. The method of claim 1,wherein the patient has been diagnosed with a complement-associateddisorder.
 10. The method of claim 9, wherein the patient has beendiagnosed with paroxysmal nocturnal hemoglobinuria (“PNH”), atypicalhemolytic uremic syndrome (“aHUS”), or Shiga-toxin-producing E. colihemolytic uremic syndrome (“STEC-HUS”).
 11. The method of claim 9,wherein the patient has been diagnosed with a complement-associateddisorder selected from the group consisting of age-related maculardegeneration, graft rejection, bone marrow rejection, kidney graftrejection, skin graft rejection, heart graft rejection, lung graftrejection, liver graft rejection, rheumatoid arthritis, a pulmonarycondition, ischemia-reperfusion injury, atypical hemolytic uremicsyndrome, thrombotic thrombocytopenic purpura, paroxysmal nocturnalhemoglobinuria, dense deposit disease, age-related macular degeneration,spontaneous fetal loss, Pauci-immune vasculitis, epidermolysis bullosa,recurrent fetal loss, multiple sclerosis, traumatic brain injury,myasthenia gravis, cold agglutinin disease, dermatomyositis, Degos'disease, Graves' disease, Hashimoto's thyroiditis, type I diabetes,psoriasis, pemphigus, autoimmune hemolytic anemia, idiopathicthrombocytopenic purpura, Goodpasture syndrome, multifocal motorneuropathy, neuromyelitis optica, antiphospholipid syndrome, sepsis,hemorrhagic fever, and catastrophic antiphospholipid syndrome.
 12. Themethod of claim 1, wherein the complement inhibitor is eculizumab or aneculizumab variant.
 13. The method of claim 1, wherein the Neisseriameningococcal type B specific vaccine is multicomponent meningococcalserogroup B vaccine (4CMenB) or meningococcal group B vaccine (Neisseriameningitidis serogroup B recombinant lp2086 a05 protein variant antigenand Neisseria meningitidis serogroup B recombinant lp2086 b01 proteinvariant antigen).
 14. A non-transitory computer-readable storage mediumstoring instructions that, when executed by a processor of a computer,cause the processor to: receive verification that a prescriberrequesting to administer a complement inhibitor has agreed to thefollowing conditions: (a) to vaccinate and/or revaccinate patientsreceiving the complement inhibitor, at predetermined times or intervals,with one or more meningococcal vaccines, including a Neisseriameningococcal type B specific vaccine; (b) to provide patients witheducational materials regarding the complement inhibitor, and (c) thatthe prescriber has reviewed information relating to administering thecomplement inhibitor; access a database of certified prescribers; addthe prescriber to the database only if the prescriber has agreed toconditions (a)-(c) in order to counsel the patient with regard to therisks associated with the complement inhibitor and is vaccinated orrevaccinated to prevent a meningococcal infection, and that theprescriber is educated with regard to administering the complementinhibitor to the patient; inspect the database of certified prescribersin response to a requisition from the prescriber requesting that theprescriber be provided with the complement inhibitor; and authorize theprescriber to prescribe the complement inhibitor only if the prescriberis in the database of certified prescribers.
 15. The medium of claim 14,wherein: an entry in the database associated with the prescriber isassociated with one or more flags certifying that the prescriber hasagreed to comply with conditions (a)-(c); and the prescriber is onlyauthorized to receive the complement inhibitor if the one or more flagsindicate that the prescriber has agreed to comply with conditions(a)-(c).
 16. The medium of claim 14, further storing instructions forprompting, after a predetermined period of time, a reminder to follow upwith the prescriber as to whether the prescriber is aware of an adverseevent associated with providing the complement inhibitor to a patient.17. The medium of claim 14, further storing instructions for prompting,after a predetermined period of time, a reminder to provide theprescriber existing or updated educational materials about thecomplement inhibitor.
 18. The medium of claim 14, further storinginstructions for transmitting, after a predetermined period of time, asurvey regarding the prescriber's compliance with one or more ofconditions (a)-(c).
 19. The medium of claim 14, further storinginstructions for: receiving a report from the prescriber that a patientwas lost to follow up; and identifying a new prescriber associated withthe patient; and performing at least one of the following: verifyingthat the new prescriber is in the database of certified prescribers, orverifying that the patient is no longer being treated with thecomplement inhibitor, and triggering a post-treatment reminder to followup with the patient regarding the occurrence of any adverse eventsfollowing discontinuation of the complement inhibitor.
 20. The medium ofclaim 14, wherein the complement inhibitor is eculizumab or aneculizumab variant.
 21. A method, comprising: receiving a request from apatient enrolled in a treatment plan employing a complement inhibitor tobe enrolled in a safety support program; adding, using a computer with aprocessor suitably programmed to perform the adding, the patient to apatient safety registry; and automatically prompting, using theprocessor, an authorized user to follow up with the patient to discussthe possibility of one or more adverse events associated with thecomplement inhibitor, the prompting instructing the authorized user todiscuss: (a) symptoms of the adverse events, and (b) whether the patienthas experienced an unreported adverse event, in order to counsel thepatient with regard to the risks associated with the adverse event whenbeing treated with the complement inhibitor, wherein the prompting isautomatically performed at one or more predetermined times or intervals.22. The method of claim 21, further comprising: accessing, using theprocessor, a database of registered nurses participating in the safetysupport program, wherein the authorized user is a registered nurse fromthe database.
 23. The method of claim 21, wherein the adverse event is ameningococcal infection.
 24. The method of claim 21, wherein theprompting further instructs the authorized user to ensure that thepatient possesses a copy of a client safety card.
 25. The method ofclaim 21, further comprising inspecting the patient registry todetermine a most-recent date of vaccination against a meningococcalinfection, including vaccination with a vaccine to Neisseriameningitidis serotype B; determining that the patient is due forrevaccination; and automatically prompting the authorized user to send arevaccination reminder to the patient.
 26. The method of claim 21,further comprising: identifying that the patient has stopped use of thecomplement inhibitor; logging the stoppage in the patient safetyregistry; and automatically prompting an updated follow-up based on arisk of adverse conditions following cessation of thecomplement-inhibitor-based treatment plan.
 27. The method of claim 21,further comprising performing a follow up by a Nurse Case Managerfollowing cessation of the complement-inhibitor-based treatment, whereinthe risk of adverse conditions is hemolysis.
 28. The method of claim 21,wherein the complement inhibitor is eculizumab or an eculizumab variant.29. A non-transitory computer-readable storage medium holdinginstructions that, when executed by a processor of a computer, cause theprocessor to: receive a request from a patient enrolled in acomplement-inhibitor-based treatment plan to be enrolled in a safetysupport program; add the patient to a patient safety registry; andautomatically prompt an authorized user to follow up with the patient todiscuss the possibility of one or more adverse events associated withthe complement inhibitor, the prompting instructing the authorized userto discuss: (a) symptoms of the adverse events, and (b) whether thepatient has experienced an unreported adverse event, in order to counselthe patient with regard to the risks associated with the adverse eventwhen being treated with the complement inhibitor, wherein the promptingis automatically performed at one or more predetermined times orintervals.
 30. The medium of claim 29, further storing instructions foraccessing, using the processor, a database of registered nursesparticipating in the safety support program, wherein the authorized useris a registered nurse from the database.
 31. The medium of claim 29,wherein the adverse event is a meningococcal infection.
 32. The mediumof claim 29, wherein the prompting further instructs the authorized userto ensure that the patient possesses a copy of a client safety card. 33.The medium of claim 29, further storing instructions for inspecting thepatient registry to determine a most-recent date of vaccination againstmeningococcal infections; determining that the patient is due forrevaccination; and prompting the authorized user to send a revaccinationreminder to the patient.
 34. The medium of claim 29, further storinginstructions for identifying that the patient has stopped use of thecomplement inhibitor; recording the stoppage in the patient safetyregistry; and automatically prompting an updated follow-up based on arisk of adverse conditions following cessation of thecomplement-inhibitor-based treatment plan.
 35. The medium of claim 29,further storing instructions for performing a follow up by a Nurse CaseManager following cessation of the complement-inhibitor-based treatment,wherein the risk of adverse conditions is hemolysis.
 36. The medium ofclaim 29, wherein the complement inhibitor is eculizumab or aneculizumab variant.
 37. A method of treating a patient in need oftreatment with a complement inhibitor, or inhibiting formation of aterminal complement in a patient, comprising: administering an effectiveamount of the complement inhibitor to said patient who has beenprescribed the complement inhibitor by a certified prescriber of thecomplement inhibitor; wherein a prescriber becomes a certifiedprescriber of the complement inhibitor by: first requesting the providerover a network, which is part of a system comprising a computer with aprocessor, to become authorized to prescribe the complement inhibitor;the provider then verifying that the prescriber has agreed to thefollowing conditions: (a) to vaccinate and/or revaccinate patientsreceiving the complement inhibitor, at predetermined times or intervals,with one or more meningococcal vaccines, including a Neisseriameningococcal type B specific vaccine; (b) to provide patients witheducational materials regarding the complement inhibitor, and (c) thatthe prescriber has reviewed information provided by the providerrelating to the complement inhibitor; once verified, adding, using theprocessor, said prescriber to the database as a certified prescriber inorder to counsel the patient with regard to the risks associated withthe complement inhibitor and is vaccinated or revaccinated to prevent ameningococcal infection, and that the prescriber is educated with regardto administering the complement inhibitor to the patient; and then usingthe processor to generate a prescription approval code and authorizing,using the processor, the prescriber to prescribe to the patient thecomplement inhibitor only if the prescriber is in the database ofcertified prescribers.